Guyton and Hall Textbook of Medical

Physiology 14th Edition John E. Hall

Visit to download the full and correct content document:
https://ebookmass.com/product/guyton-and-hall-textbook-of-medical-physiology-14th-
edition-john-e-hall-2/
NOTE TO INSTRUCTORS
Contact your Elsevier Sales Representative for teaching
resources, including slides and image banks, for Guyton and
Hall Textbook of ­Medical Physiology, 14e, or request these
supporting materials at:
http://evolve.elsevier.com/Hall/physiology/
 14TH EDITION

Guyton and Hall

Textbook of Medical Physiology

John E. Hall, PhD

Arthur C. Guyton Professor and Chair
Department of Physiology and Biophysics
Director, Mississippi Center for Obesity Research
University of Mississippi Medical Center
Jackson, Mississippi

Michael E. Hall, MD, MS

Associate Professor
Department of Medicine, Division of
Cardiovascular Diseases
Associate Vice Chair for Research
Department of Physiology and Biophysics
University of Mississippi Medical Center
Jackson, Mississippi
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-­2899

GUYTON AND HALL TEXTBOOK OF MEDICAL PHYSIOLOGY,

FOURTEENTH EDITION  ISBN: 978-­0-­323-­59712-­8
INTERNATIONAL EDITION  ISBN: 978-­0-­323-­67280-­1

Copyright © 2021 by Elsevier, Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Notice

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds or experiments described herein. Because of rapid advances
in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be
made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or
contributors for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.

Previous editions copyrighted 2016, 2011, 2006, 2000, 1996, 1991, 1986, 1981, 1976, 1971, 1966, 1961, and 1956.

Library of Congress Control Number: 2020936245

Publisher: Elyse O’Grady

Senior Content Development Specialist: Jennifer Shreiner
Publishing Services Manager: Julie Eddy
Project Manager: Grace Onderlinde
Design Direction: Margaret Reid

Printed in Canada

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 To
Our Families
For their abundant support, for their patience and
understanding, and for their love

To
Arthur C. Guyton
For his imaginative and innovative research
For his dedication to education
For showing us the excitement and joy of physiology
And for serving as an inspirational role model

The first edition of the Textbook of Medical Physiology was
written by Arthur C. Guyton almost 65 years ago. Unlike
most major medical textbooks, which often have 20 or
more authors, the first eight editions of the Textbook of
Medical Physiology were written entirely by Dr. Guyton.
He had a gift for communicating complex ideas in a clear
and interesting manner that made studying physiology
fun. He wrote the book to help students learn physiology,
not to impress his professional colleagues.
Dr. John Hall worked closely with Dr. Guyton for
almost 30 years and had the privilege of writing parts of
the 9th and 10th editions and of assuming sole responsi-
bility for completing the subsequent editions.
Dr. Michael Hall has joined in the preparation of the
14th edition of the Textbook of Medical Physiology. He is
a physician trained in internal medicine, cardiology, and
physiology and has brought new insights that have helped
greatly to achieve the same goal as for previous editions—
to explain, in language easily understood by students, how
the different cells, tissues, and organs of the human body
work together to maintain life.
This task has been challenging and fun because
researchers continue to unravel new mysteries of body
functions. Advances in molecular and cellular physiology
have made it possible to explain some physiology princi-
ples in the terminology of molecular and physical sciences
rather than in merely a series of separate and unexplained
biological phenomena. However, the molecular events
that underpin the functions of the body’s cells provide
only a partial explanation of human physiology. The total
function of the human body requires complex control
systems that communicate with each other and coordi-
nate the molecular functions of the body’s cells, tissues,
and organs in health and disease.
The Textbook of Medical Physiology is not a reference
book that attempts to provide a compendium of the most
recent advances in physiology. It is a book that contin-
ues the tradition of being written for students. It focuses
on the basic principles of physiology needed to begin a
career in the health care professions, such as medicine,
dentistry, and nursing, as well as graduate studies in the
biological and health sciences. It should also be useful
to physicians and health care professionals who wish to
Preface
review the basic principles needed for understanding the
pathophysiology of human disease. We have attempted to
maintain the same unified organization of the text that
has been useful to students in the past and to ensure that
the book is comprehensive enough that students will con-
tinue to use it during their professional careers.
Our hope is that the Textbook of Medical Physiology
conveys the majesty of the human body and its many
functions and that it stimulates students to study physiol-
ogy throughout their careers. Physiology links the basic
sciences and medicine. The great beauty of physiology is
that it integrates the individual functions of all the body’s
different cells, tissues, and organs into a functional whole,
the human body. Indeed, the human body is much more
than the sum of its parts, and life relies upon this total
function, not just on the function of individual body parts
in isolation from the others.
This brings us to an important question: How are the
separate organs and systems coordinated to maintain
proper function of the entire body? Fortunately, our bod-
ies are endowed with a vast network of feedback controls
that achieve the necessary balances without which we
would be unable to live. Physiologists call this high level
of internal bodily control homeostasis. In disease states,
functional balances are often seriously disturbed, and
homeostasis is impaired. When even a single disturbance
reaches a limit, the whole body can no longer live. One of
the goals of this text is to emphasize the effectiveness and
beauty of the body’s homeostasis mechanisms as well as
to present their abnormal functions in disease.
Another objective is to be as accurate as possible. Sug-
gestions and critiques from many students, physiologists,
and clinicians throughout the world have checked factual
accuracy as well as balance in the text. Even so, because
of the likelihood of error in sorting through many thou-
sands of bits of information, we issue a further request
for all readers to send notations of error or inaccuracy to
us. Physiologists understand the importance of feedback
for proper function of the human body; feedback is also
important for progressive improvement of a textbook of
physiology. To the many persons who have already helped,
we express sincere thanks. Your feedback has helped to
improve the text.
vii
Preface
A brief explanation is needed about several features
of the 14th edition. Although many of the chapters have
been revised to include new principles of physiology and
new figures to illustrate these principles, the text length
has been closely monitored to limit the book’s size so
that it can be used effectively in physiology courses for
medical students and health care professionals. New
references have been chosen primarily for their pre-
sentation of physiological principles, for the quality of
their own references, and for their easy accessibility.
The selected bibliography at the end of the chapters lists
mainly review papers from recently published scientific
journals that can be freely accessed from the PubMed site
at https://www.ncbi.nlm.nih.gov/pubmed/. Use of these
references, as well as cross-­references from them, pro-
vides much more extensive coverage of the entire field of
physiology.
Our effort to be as concise as possible has, unfortu-
nately, necessitated a more simplified and dogmatic
presentation of many physiological principles than we
normally would have desired. However, the bibliogra-
phy can be used to learn more about the controversies
and unanswered questions that remain in understanding
the complex functions of the human body in health and
disease.
Another feature of the book is that the print is set
in two sizes. The material in large print constitutes the
fundamental physiological information that students
will require in virtually all of their medical studies. The
material in small print and highlighted with a pale lav-
ender background (or identified by beginning and ending
double gray arrowheads in the ebook version) is of several
different kinds: (1) anatomic, chemical, and other infor-
mation that is needed for immediate discussion but that
viii
most students will learn in more detail in other courses;
(2) physiological information of special importance to
certain fields of clinical medicine; and (3) information
that will be of value to those students who wish to study
specific physiological mechanisms more deeply.
The ebook version provides links to additional content
including video animations and self-­assessment questions
that can be accessed with computers, smart phones, and
electronic tablets. For additional self-­assessment beyond
these textbook supplements, the reader may consider
using a copy of Guyton and Hall Physiology Review, which
includes more than 1000 practice questions referenced to
the textbook. We hope that these ancillary materials will
assist readers in testing their understanding of basic prin-
ciples of physiology.
We express sincere thanks to many persons who have
helped to prepare this book, including our colleagues in
the Department of Physiology and Biophysics at the Uni-
versity of Mississippi Medical Center who provided valu-
able suggestions. The members of our faculty and a brief
description of the research and educational activities of the
department can be found at http://physiology.umc.edu/.
We are especially grateful to Stephanie Lucas for excellent
assistance and to James Perkins for excellent illustrations.
We also thank Elyse O’Grady, Jennifer Shreiner, Grace
Onderlinde, Rebecca Gruliow, and the entire Elsevier
team for continued editorial and production excellence.
Finally, we thank the many readers who continue to
help us improve the Textbook of Medical Physiology. We
hope that you enjoy the current edition and find it even
more useful than previous editions.
John E. Hall
Michael E. Hall

Functional Organization of the Human Body
and Control of the “Internal Environment”
Physiology is the science that seeks to explain the physi-
cal and chemical mechanisms that are responsible for the
origin, development, and progression of life. Each type
of life, from the simplest virus to the largest tree or the
complicated human being, has its own functional char-
acteristics. Therefore, the vast field of physiology can be
divided into viral physiology, bacterial physiology, cellular
physiology, plant physiology, invertebrate physiology, ver-
tebrate physiology, mammalian physiology, human physi-
ology, and many more subdivisions.
Human Physiology. The science of human physiology
attempts to explain the specific characteristics and mech-
anisms of the human body that make it a living being. The
fact that we remain alive is the result of complex control
systems. Hunger makes us seek food, and fear makes us
seek refuge. Sensations of cold make us look for warmth.
Other forces cause us to seek fellowship and to reproduce.
The fact that we are sensing, feeling, and knowledgeable
beings is part of this automatic sequence of life; these spe-
cial attributes allow us to exist under widely varying con-
ditions that otherwise would make life impossible.
Human physiology links the basic sciences with medicine
and integrates multiple functions of the cells, tissues, and
organs into the functions of the living human being. This inte-
gration requires communication and coordination by a vast
array of control systems that operate at every level—from the
genes that program synthesis of molecules to the complex
nervous and hormonal systems that coordinate functions of
cells, tissues, and organs throughout the body. Thus, the coor-
dinated functions of the human body are much more than the
sum of its parts, and life in health, as well as in disease states,
relies on this total function. Although the main focus of this
book is on normal human physiology, we will also discuss,
to some extent, pathophysiology, which is the study of disor-
dered body function and the basis for clinical medicine.
CELLS ARE THE LIVING UNITS OF THE
BODY
The basic living unit of the body is the cell. Each tissue or
organ is an aggregate of many different cells held together
by intercellular supporting structures.
CHAPTER 1
UNIT I
Each type of cell is specially adapted to perform one
or a few particular functions. For example, the red blood
cells, numbering about 25 trillion in each person, trans-
port oxygen from the lungs to the tissues. Although the
red blood cells are the most abundant of any single type of
cell in the body, there are also trillions of additional cells
of other types that perform functions different from those
of the red blood cell. The entire body, then, contains about
35 to 40 trillion human cells.
The many cells of the body often differ markedly from
one another but all have certain basic characteristics that
are alike. For example, oxygen reacts with carbohydrate,
fat, and protein to release the energy required for all cells
to function. Furthermore, the general chemical mecha-
nisms for changing nutrients into energy are basically
the same in all cells, and all cells deliver products of their
chemical reactions into the surrounding fluids.
Almost all cells also have the ability to reproduce addi-
tional cells of their own type. Fortunately, when cells of a
particular type are destroyed, the remaining cells of this type
usually generate new cells until the supply is replenished.
Microorganisms Living in the Body Outnumber Hu-
man Cells. In addition to human cells, trillions of microbes
inhabit the body, living on the skin and in the mouth, gut,
and nose. The gastrointestinal tract, for example, normally
contains a complex and dynamic population of 400 to 1000
species of microorganisms that outnumber our human
cells. Communities of microorganisms that inhabit the
body, often called microbiota, can cause diseases, but most
of the time they live in harmony with their human hosts
and provide vital functions that are essential for survival of
their hosts. Although the importance of gut microbiota in
the digestion of foodstuffs is widely recognized, additional
roles for the body’s microbes in nutrition, immunity, and
other functions are just beginning to be appreciated and
represent an intensive area of biomedical research.
EXTRACELLULAR FLUID—THE
“INTERNAL ENVIRONMENT”
About 50% to 70% of the adult human body is fluid, mainly
a water solution of ions and other substances. Although
3
UNIT I Introduction to Physiology: The Cell and General Physiology
most of this fluid is inside the cells and is called intracellu-
lar fluid, about one-­third is in the spaces outside the cells
and is called extracellular fluid. This extracellular fluid is
in constant motion throughout the body. It is transported
rapidly in the circulating blood and then mixed between
the blood and tissue fluids by diffusion through the capil-
lary walls.
In the extracellular fluid are the ions and nutrients
needed by the cells to maintain life. Thus, all cells live in
essentially the same environment—the extracellular fluid.
For this reason, the extracellular fluid is also called the
internal environment of the body, or the milieu intérieur, a
term introduced by the great 19th-­century French physi-
ologist Claude Bernard (1813–1878).
Cells are capable of living and performing their spe-
cial functions as long as the proper concentrations of
oxygen, glucose, different ions, amino acids, fatty sub-
stances, and other constituents are available in this inter-
nal environment.
Differences in Extracellular and Intracellular Fluids.
The extracellular fluid contains large amounts of sodium,
chloride, and bicarbonate ions plus nutrients for the cells,
such as oxygen, glucose, fatty acids, and amino acids. It
also contains carbon dioxide that is being transported
from the cells to the lungs to be excreted, plus other cel-
lular waste products that are being transported to the kid-
neys for excretion.
The intracellular fluid contains large amounts of potas-
sium, magnesium, and phosphate ions instead of the
sodium and chloride ions found in the extracellular fluid.
Special mechanisms for transporting ions through the cell
membranes maintain the ion concentration differences
between the extracellular and intracellular fluids. These
transport processes are discussed in Chapter 4.
HOMEOSTASIS—MAINTENANCE OF
A NEARLY CONSTANT INTERNAL
ENVIRONMENT
In 1929, the American physiologist Walter Cannon
(1871–1945) coined the term homeostasis to describe the
maintenance of nearly constant conditions in the internal
environment. Essentially, all organs and tissues of the body
perform functions that help maintain these relatively con-
stant conditions. For example, the lungs provide oxygen
to the extracellular fluid to replenish the oxygen used by
the cells, the kidneys maintain constant ion concentra-
tions, and the gastrointestinal system provides nutrients
while eliminating waste from the body.
The various ions, nutrients, waste products, and other
constituents of the body are normally regulated within a
range of values, rather than at fixed values. For some of the
body’s constituents, this range is extremely small. Varia-
tions in the blood hydrogen ion concentration, for exam-
ple, are normally less than 5 nanomoles/L (0.000000005
moles/L). The blood sodium concentration is also tightly
4
regulated, normally varying only a few millimoles per liter,
even with large changes in sodium intake, but these varia-
tions of sodium concentration are at least 1 million times
greater than for hydrogen ions.
Powerful control systems exist for maintaining concen-
trations of sodium and hydrogen ions, as well as for most
of the other ions, nutrients, and substances in the body at
levels that permit the cells, tissues, and organs to perform
their normal functions, despite wide environmental varia-
tions and challenges from injury and diseases.
Much of this text is concerned with how each organ or
tissue contributes to homeostasis. Normal body functions
require integrated actions of cells, tissues, organs, and
multiple nervous, hormonal, and local control systems
that together contribute to homeostasis and good health.
Homeostatic Compensations in Diseases. Disease is
often considered to be a state of disrupted homeostasis.
However, even in the presence of disease, homeostatic
mechanisms continue to operate and maintain vital func-
tions through multiple compensations. In some cases,
these compensations may lead to major deviations of the
body’s functions from the normal range, making it diffi-
cult to distinguish the primary cause of the disease from
the compensatory responses. For example, diseases that
impair the kidneys’ ability to excrete salt and water may
lead to high blood pressure, which initially helps return
excretion to normal so that a balance between intake and
renal excretion can be maintained. This balance is needed
to maintain life, but, over long periods of time, the high
blood pressure can damage various organs, including the
kidneys, causing even greater increases in blood pressure
and more renal damage. Thus, homeostatic compensa-
tions that ensue after injury, disease, or major environ-
mental challenges to the body may represent trade-­offs
that are necessary to maintain vital body functions but,
in the long term, contribute to additional abnormalities
of body function. The discipline of pathophysiology seeks
to explain how the various physiological processes are al-
tered in diseases or injury.
This chapter outlines the different functional systems
of the body and their contributions to homeostasis. We
then briefly discuss the basic theory of the body’s control
systems that allow the functional systems to operate in
support of one another.
EXTRACELLULAR FLUID TRANSPORT
AND MIXING SYSTEM—THE BLOOD
CIRCULATORY SYSTEM
Extracellular fluid is transported through the body in two
stages. The first stage is movement of blood through the
body in the blood vessels. The second is movement of
fluid between the blood capillaries and the intercellular
spaces between the tissue cells.
Figure 1-1 shows the overall circulation of blood. All the
blood in the circulation traverses the entire circuit an average
 Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment”

Lungs Arteriole

UNIT I
CO2 O2
Right Left
heart heart
pump pump
Venule

Gut

Figure 1-2. Diffusion of fluid and dissolved constituents through the

capillary walls and interstitial spaces.

Nutrition That is, the fluid and dissolved molecules are continually
and moving and bouncing in all directions in the plasma and
excretion
fluid in the intercellular spaces, as well as through capil-
lary pores. Few cells are located more than 50 microm-
eters from a capillary, which ensures diffusion of almost
any substance from the capillary to the cell within a few
Kidneys
seconds. Thus, the extracellular fluid everywhere in the
body—both that of the plasma and that of the interstitial
fluid—is continually being mixed, thereby maintaining
homogeneity of extracellular fluid throughout the body.

Regulation ORIGIN OF NUTRIENTS IN THE

of Excretion
electrolytes
Venous end Arterial end
Capillaries
Figure 1-1. General organization of the circulatory system.
of once each minute when the body is at rest and as many
as six times each minute when a person is extremely active.
As blood passes through blood capillaries, continual
exchange of extracellular fluid occurs between the plasma
portion of the blood and the interstitial fluid that fills the
intercellular spaces. This process is shown in Figure 1-2.
The capillary walls are permeable to most molecules in
the blood plasma, with the exception of plasma proteins,
which are too large to pass through capillaries readily.
Therefore, large amounts of fluid and its dissolved con-
stituents diffuse back and forth between the blood and the
tissue spaces, as shown by the arrows in Figure 1-2.
This process of diffusion is caused by kinetic motion
of the molecules in the plasma and the interstitial fluid.
EXTRACELLULAR FLUID
Respiratory System. Figure 1-1 shows that each time
blood passes through the body, it also flows through the
lungs. The blood picks up oxygen in alveoli, thus acquiring
the oxygen needed by cells. The membrane between the
alveoli and the lumen of the pulmonary capillaries, the
alveolar membrane, is only 0.4 to 2.0 micrometers thick,
and oxygen rapidly diffuses by molecular motion through
this membrane into the blood.
Gastrointestinal Tract. A large portion of the blood pumped
by the heart also passes through the walls of the gastrointes-
tinal tract. Here different dissolved nutrients, including car-
bohydrates, fatty acids, and amino acids, are absorbed from
ingested food into the extracellular fluid of the blood.
Liver and Other Organs That Perform Primarily Meta-
bolic Functions. Not all substances absorbed from the
gastrointestinal tract can be used in their absorbed form
by the cells. The liver changes the chemical compositions
of many of these substances to more usable forms, and
other tissues of the body—fat cells, gastrointestinal mu-
cosa, kidneys, and endocrine glands—help modify the
absorbed substances or store them until they are needed.
The liver also eliminates certain waste products produced
in the body and toxic substances that are ingested.

5
UNIT I Introduction to Physiology: The Cell and General Physiology
Musculoskeletal System. How does the musculoskeletal
system contribute to homeostasis? The answer is obvious
and simple. Were it not for the muscles, the body could
not move to obtain the foods required for nutrition. The
musculoskeletal system also provides motility for protec-
tion against adverse surroundings, without which the en-
tire body, along with its homeostatic mechanisms, could
be destroyed.
REMOVAL OF METABOLIC END PRODUCTS
Removal of Carbon Dioxide by the Lungs. At the same
time that blood picks up oxygen in the lungs, carbon di-
oxide is released from the blood into lung alveoli; the res-
piratory movement of air into and out of the lungs carries
carbon dioxide to the atmosphere. Carbon dioxide is the
most abundant of all the metabolism products.
Kidneys. Passage of blood through the kidneys removes
most of the other substances from the plasma besides car-
bon dioxide that are not needed by cells. These substanc-
es include different end products of cellular metabolism,
such as urea and uric acid; they also include excesses of
ions and water from the food that accumulate in the ex-
tracellular fluid.
The kidneys perform their function first by filtering
large quantities of plasma through the glomerular capil-
laries into the tubules and then reabsorbing into the blood
substances needed by the body, such as glucose, amino
acids, appropriate amounts of water, and many of the
ions. Most of the other substances that are not needed
by the body, especially metabolic waste products such
as urea and creatinine, are reabsorbed poorly and pass
through the renal tubules into the urine.
Gastrointestinal Tract. Undigested material that enters
the gastrointestinal tract and some waste products of me-
tabolism are eliminated in the feces.
Liver. Among the many functions of the liver is detoxifi-
cation or removal of ingested drugs and chemicals. The
liver secretes many of these wastes into the bile to be
eventually eliminated in the feces.
REGULATION OF BODY FUNCTIONS
Nervous System. The nervous system is composed of
three major parts—the sensory input portion, the central
nervous system (or integrative portion), and the motor out-
put portion. Sensory receptors detect the state of the body
and its surroundings. For example, receptors in the skin
alert us whenever an object touches the skin. The eyes
are sensory organs that give us a visual image of the sur-
rounding area. The ears are also sensory organs. The cen-
tral nervous system is composed of the brain and spinal
cord. The brain stores information, generates thoughts,
creates ambition, and determines reactions that the body
6
performs in response to the sensations. Appropriate sig-
nals are then transmitted through the motor output por-
tion of the nervous system to carry out one’s desires.
An important segment of the nervous system is called
the autonomic system. It operates at a subconscious level
and controls many functions of internal organs, including
the level of pumping activity by the heart, movements of
the gastrointestinal tract, and secretion by many of the
body’s glands.
Hormone Systems. Located in the body are endocrine
glands, organs and tissues that secrete chemical sub-
stances called hormones. Hormones are transported in
the extracellular fluid to other parts of the body to help
regulate cellular function. For example, thyroid hormone
increases the rates of most chemical reactions in all cells,
thus helping set the tempo of bodily activity. Insulin con-
trols glucose metabolism, adrenocortical hormones con-
trol sodium and potassium ions and protein metabolism,
and parathyroid hormone controls bone calcium and
phosphate. Thus, the hormones provide a regulatory sys-
tem that complements the nervous system. The nervous
system controls many muscular and secretory activities
of the body, whereas the hormonal system regulates many
metabolic functions. The nervous and hormonal systems
normally work together in a coordinated manner to con-
trol essentially all the organ systems of the body.
PROTECTION OF THE BODY
Immune System. The immune system includes white
blood cells, tissue cells derived from white blood cells, the
thymus, lymph nodes, and lymph vessels that protect the
body from pathogens such as bacteria, viruses, parasites,
and fungi. The immune system provides a mechanism for
the body to carry out the following: (1) distinguish its own
cells from harmful foreign cells and substances; and (2)
destroy the invader by phagocytosis or by producing sensi-
tized lymphocytes or specialized proteins (e.g., antibodies)
that destroy or neutralize the invader.
Integumentary System. The skin and its various ap-
pendages (including the hair, nails, glands, and other
structures) cover, cushion, and protect the deeper tissues
and organs of the body and generally provide a bound-
ary between the body’s internal environment and the out-
side world. The integumentary system is also important
for temperature regulation and excretion of wastes, and
it provides a sensory interface between the body and the
external environment. The skin generally comprises about
12% to 15% of body weight.
REPRODUCTION
Although reproduction is sometimes not considered a
homeostatic function, it helps maintain homeostasis by
generating new beings to take the place of those that are
 Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment”
dying. This may sound like a permissive usage of the term
homeostasis, but it illustrates that in the final analysis,
essentially all body structures are organized to help main-
tain the automaticity and continuity of life.
CONTROL SYSTEMS OF THE BODY
The human body has thousands of control systems. Some
of the most intricate of these systems are genetic control
systems that operate in all cells to help regulate intracel-
lular and extracellular functions. This subject is discussed
in Chapter 3.
Many other control systems operate within the organs
to regulate functions of the individual parts of the organs;
others operate throughout the entire body to control the
interrelationships between the organs. For example, the
respiratory system, operating in association with the
nervous system, regulates the concentration of carbon
dioxide in the extracellular fluid. The liver and pancreas
control glucose concentration in the extracellular fluid,
and the kidneys regulate concentrations of hydrogen,
sodium, potassium, phosphate, and other ions in the
extracellular fluid.
EXAMPLES OF CONTROL MECHANISMS
Regulation of Oxygen and Carbon Dioxide Concen-
trations in the Extracellular Fluid. Because oxygen is
one of the major substances required for chemical reac-
tions in cells, the body has a special control mechanism to
maintain an almost exact and constant oxygen concentra-
tion in the extracellular fluid. This mechanism depends
principally on the chemical characteristics of hemoglobin,
which is present in red blood cells. Hemoglobin com-
bines with oxygen as the blood passes through the lungs.
Then, as the blood passes through the tissue capillaries,
hemoglobin, because of its own strong chemical affinity
for oxygen, does not release oxygen into the tissue fluid
if too much oxygen is already there. However, if oxygen
concentration in the tissue fluid is too low, sufficient oxy-
gen is released to re-­establish an adequate concentration.
Thus, regulation of oxygen concentration in the tissues
relies to a great extent on the chemical characteristics of
hemoglobin. This regulation is called the oxygen-­buffering
function of hemoglobin.
Carbon dioxide concentration in the extracellular fluid
is regulated in a much different way. Carbon dioxide is a
major end product of oxidative reactions in cells. If all the
carbon dioxide formed in the cells continued to accumu-
late in the tissue fluids, all energy-­giving reactions of the
cells would cease. Fortunately, a higher than normal car-
bon dioxide concentration in the blood excites the respira-
tory center, causing a person to breathe rapidly and deeply.
This deep rapid breathing increases expiration of carbon
dioxide and, therefore, removes excess carbon dioxide
from the blood and tissue fluids. This process continues
until the concentration returns to normal.
Reference
set point
Error signal Effectors
Brain medulla
Sympathetic Blood vessels
Vasomotor
nervous system Heart
centers
UNIT I
Feedback signal
Baroreceptors Arterial
pressure
Sensor Controlled variable
Figure 1-3. Negative feedback control of arterial pressure by the ar-
terial baroreceptors. Signals from the sensor (baroreceptors) are sent
to the medulla of the brain, where they are compared with a refer-
ence set point. When arterial pressure increases above normal, this
abnormal pressure increases nerve impulses from the baroreceptors
to the medulla of the brain, where the input signals are compared
with the set point, generating an error signal that leads to decreased
sympathetic nervous system activity. Decreased sympathetic activity
causes dilation of blood vessels and reduced pumping activity of the
heart, which return arterial pressure toward normal.
Regulation of Arterial Blood Pressure. Several systems
contribute to arterial blood pressure regulation. One of
these, the baroreceptor system, is an excellent example of
a rapidly acting control mechanism (Figure 1-3). In the
walls of the bifurcation region of the carotid arteries in
the neck, and also in the arch of the aorta in the thorax,
are many nerve receptors called baroreceptors that are
stimulated by stretch of the arterial wall. When arterial
pressure rises too high, the baroreceptors send barrages
of nerve impulses to the medulla of the brain. Here, these
impulses inhibit the vasomotor center, which in turn de-
creases the number of impulses transmitted from the
vasomotor center through the sympathetic nervous sys-
tem to the heart and blood vessels. Lack of these impulses
causes diminished pumping activity by the heart and dila-
tion of peripheral blood vessels, allowing increased blood
flow through the vessels. Both these effects decrease the
arterial pressure, moving it back toward normal.
Conversely, a decrease in arterial pressure below nor-
mal relaxes the stretch receptors, allowing the vasomotor
center to become more active than usual, thereby causing
vasoconstriction and increased heart pumping. The initial
decrease in arterial pressure thus initiates negative feed-
back mechanisms that raise arterial pressure back toward
normal.
Normal Ranges and Physical
Characteristics of Important Extracellular
Fluid Constituents
Table 1-1 lists some important constituents and physical
characteristics of extracellular fluid, along with their nor-
mal values, normal ranges, and maximum limits without
causing death. Note the narrowness of the normal range
for each one. Values outside these ranges are often caused
by illness, injury, or major environmental challenges.
7
UNIT I Introduction to Physiology: The Cell and General Physiology

Table 1-1  Important Constituents and Physical Characteristics of Extracellular Fluid

Constituent Normal Value Normal Range Approximate Short-­Term Nonlethal Limit Unit
Oxygen (venous) 40 25–40 10–1000 mm Hg
Carbon dioxide (venous) 45 41–51 5–80 mm Hg
Sodium ion 142 135–145 115–175 mmol/L
Potassium ion 4.2 3.5–5.3 1.5–9.0 mmol/L
Calcium ion 1.2 1.0–1.4 0.5–2.0 mmol/L
Chloride ion 106 98–108 70–130 mmol/L
Bicarbonate ion 24 22–29 8–45 mmol/L
Glucose 90 70–115 20–1500 mg/dl
Body temperature 98.4 (37.0) 98–98.8 (37.0) 65–110 (18.3–43.3) °F (°C)
Acid–base (venous) 7.4 7.3–7.5 6.9–8.0 pH

Most important are the limits beyond which abnor-
malities can cause death. For example, an increase in the
body temperature of only 11°F (7°C) above normal can
lead to a vicious cycle of increasing cellular metabolism
that destroys the cells. Note also the narrow range for
acid–base balance in the body, with a normal pH value
of 7.4 and lethal values only about 0.5 on either side of
normal. Whenever the potassium ion concentration
decreases to less than one-­third normal, paralysis may
result from the inability of the nerves to carry signals.
Alternatively, if potassium ion concentration increases
to two or more times normal, the heart muscle is likely
to be severely depressed. Also, when the calcium ion
concentration falls below about one-­half normal, a per-
son is likely to experience tetanic contraction of muscles
throughout the body because of the spontaneous genera-
tion of excess nerve impulses in peripheral nerves. When
the glucose concentration falls below one-­half normal, a
person frequently exhibits extreme mental irritability and
sometimes even has convulsions.
These examples should give one an appreciation for
the necessity of the vast numbers of control systems that
keep the body operating in health. In the absence of any
one of these controls, serious body malfunction or death
can result.
CHARACTERISTICS OF CONTROL SYSTEMS
The aforementioned examples of homeostatic control
mechanisms are only a few of the many thousands in the
body, all of which have some common characteristics, as
explained in this section.
Negative Feedback Nature of Most
Control Systems
Most control systems of the body act by negative feed-
back, which can be explained by reviewing some of the
homeostatic control systems mentioned previously. In
the regulation of carbon dioxide concentration, a high
concentration of carbon dioxide in the extracellular fluid
increases pulmonary ventilation. This, in turn, decreases
the extracellular fluid carbon dioxide concentration
because the lungs expire greater amounts of carbon diox-
ide from the body. Thus, the high concentration of carbon
dioxide initiates events that decrease the concentration
toward normal, which is negative to the initiating stimu-
lus. Conversely, a carbon dioxide concentration that falls
too low results in feedback to increase the concentration.
This response is also negative to the initiating stimulus.
In the arterial pressure–regulating mechanisms, a high
pressure causes a series of reactions that promote reduced
pressure, or a low pressure causes a series of reactions that
promote increased pressure. In both cases, these effects
are negative with respect to the initiating stimulus.
Therefore, in general, if some factor becomes exces-
sive or deficient, a control system initiates negative feed-
back, which consists of a series of changes that return
the factor toward a certain mean value, thus maintaining
homeostasis.
Gain of a Control System. The degree of effectiveness
with which a control system maintains constant condi-
tions is determined by the gain of negative feedback.
For example, let us assume that a large volume of blood
is transfused into a person whose baroreceptor pressure
control system is not functioning, and the arterial pres-
sure rises from the normal level of 100 mm Hg up to 175
mm Hg. Then, let us assume that the same volume of
blood is injected into the same person when the barore-
ceptor system is functioning, and this time the pressure
increases by only 25 mm Hg. Thus, the feedback control
system has caused a “correction” of −50 mm Hg, from
175 mm Hg to 125 mm Hg. There remains an increase in
pressure of +25 mm Hg, called the “error,” which means
that the control system is not 100% effective in preventing
change. The gain of the system is then calculated by using
the following formula:
Correction
Gain =
Error
Thus, in the baroreceptor system example, the correc-
tion is −50 mm Hg, and the error persisting is +25 mm Hg.
Therefore, the gain of the person’s baroreceptor system

8
 Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment”
5 overcome by the negative feedback control mechanisms
Pumping effectiveness of heart
Return to
(Liters pumped per minute)
4 normal
Bled 1 liter
3 arterial pressure can counterbalance the positive feedback
Bled 2 liters
2
1 sometimes uses positive feedback to its advantage. Blood
Death
0
1 2
Hours
Figure 1-4. Recovery of heart pumping caused by negative feedback
after 1 liter of blood is removed from the circulation. Death is caused
by positive feedback when 2 liters or more blood is removed.
for control of arterial pressure is −50 divided by +25, or
−2. That is, a disturbance that increases or decreases the
arterial pressure does so only one-third as much as would
occur if this control system were not present.
The gains of some other physiological control systems
are much greater than that of the baroreceptor system.
For example, the gain of the system controlling internal
body temperature when a person is exposed to moder-
ately cold weather is about −33. Therefore, one can see
that the temperature control system is much more effec-
tive than the baroreceptor pressure control system.
Positive Feedback May Cause Vicious
Cycles and Death
Why do most control systems of the body operate by
negative feedback rather than by positive feedback? If
one considers the nature of positive feedback, it is obvi-
ous that positive feedback leads to instability rather than
stability and, in some cases, can cause death.
Figure 1-4 shows an example in which death can ensue
from positive feedback. This figure depicts the pumping
effectiveness of the heart, showing the heart of a healthy
human pumping about 5 liters of blood per minute. If the
person suddenly bleeds a total of 2 liters, the amount of
blood in the body is decreased to such a low level that
not enough blood is available for the heart to pump effec-
tively. As a result, the arterial pressure falls, and the flow
of blood to the heart muscle through the coronary ves-
sels diminishes. This scenario results in weakening of the
heart, further diminished pumping, a further decrease
in coronary blood flow, and still more weakness of the
heart; the cycle repeats itself again and again until death
occurs. Note that each cycle in the feedback results in
further weakening of the heart. In other words, the initi-
ating stimulus causes more of the same, which is positive
feedback.
Positive feedback is sometimes known as a “vicious
cycle,” but a mild degree of positive feedback can be
of the body, and the vicious cycle then fails to develop.
For example, if the person in the aforementioned example
bleeds only 1 liter instead of 2 liters, the normal negative
feedback mechanisms for controlling cardiac output and
UNIT I
and the person can recover, as shown by the dashed curve
of Figure 1-4.
Positive Feedback Can Sometimes Be Useful. The body
clotting is an example of a valuable use of positive feed-
back. When a blood vessel is ruptured, and a clot begins to
form, multiple enzymes called clotting factors are activated
3
within the clot. Some of these enzymes act on other inac-
tivated enzymes of the immediately adjacent blood, thus
causing more blood clotting. This process continues until
the hole in the vessel is plugged and bleeding no longer
occurs. On occasion, this mechanism can get out of hand
and cause formation of unwanted clots. In fact, this is what
initiates most acute heart attacks, which can be caused by
a clot beginning on the inside surface of an atherosclerotic
plaque in a coronary artery and then growing until the ar-
tery is blocked.
Childbirth is another situation in which positive feed-
back is valuable. When uterine contractions become
strong enough for the baby’s head to begin pushing
through the cervix, stretching of the cervix sends signals
through the uterine muscle back to the body of the uterus,
causing even more powerful contractions. Thus, the uter-
ine contractions stretch the cervix, and cervical stretch
causes stronger contractions. When this process becomes
powerful enough, the baby is born. If they are not pow-
erful enough, the contractions usually die out, and a few
days pass before they begin again.
Another important use of positive feedback is for the
generation of nerve signals. Stimulation of the mem-
brane of a nerve fiber causes slight leakage of sodium ions
through sodium channels in the nerve membrane to the
fiber’s interior. The sodium ions entering the fiber then
change the membrane potential, which, in turn, causes
more opening of channels, more change of potential, still
more opening of channels, and so forth. Thus, a slight leak
becomes an explosion of sodium entering the interior of
the nerve fiber, which creates the nerve action potential.
This action potential, in turn, causes electrical current to
flow along the outside and inside of the fiber and initiates
additional action potentials. This process continues until
the nerve signal goes all the way to the end of the fiber.
In each case in which positive feedback is useful, the
positive feedback is part of an overall negative feedback
process. For example, in the case of blood clotting, the
positive feedback clotting process is a negative feedback
process for the maintenance of normal blood volume.
Also, the positive feedback that causes nerve signals
allows the nerves to participate in thousands of negative
feedback nervous control systems.
9
UNIT I Introduction to Physiology: The Cell and General Physiology
More Complex Types of Control
Systems—Feed-­Forward and Adaptive
Control
Later in this text, when we study the nervous system, we
shall see that this system contains great numbers of inter-
connected control mechanisms. Some are simple feedback
systems similar to those already discussed. Many are not.
For example, some movements of the body occur so rap-
idly that there is not enough time for nerve signals to travel
from the peripheral parts of the body all the way to the
brain and then back to the periphery again to control the
movement. Therefore, the brain uses a mechanism called
feed-­forward control to cause required muscle contrac-
tions. Sensory nerve signals from the moving parts apprise
the brain about whether the movement is performed cor-
rectly. If not, the brain corrects the feed-­forward signals
that it sends to the muscles the next time the movement
is required. Then, if still further correction is necessary,
this process will be performed again for subsequent move-
ments. This process is called adaptive control. Adaptive
control, in a sense, is delayed negative feedback.
Thus, one can see how complex the feedback control
systems of the body can be. A person’s life depends on all
of them. Therefore, much of this text is devoted to dis-
cussing these life-­giving mechanisms.
PHYSIOLOGICAL VARIABILITY
Although some physiological variables, such as plasma
concentrations of potassium, calcium, and hydrogen
ions, are tightly regulated, others, such as body weight
and adiposity, show wide variation among different indi-
viduals and even in the same individual at different stages
of life. Blood pressure, cardiac pumping, metabolic rate,
nervous system activity, hormones, and other physi-
ological variables change throughout the day as we move
about and engage in normal daily activities. Therefore,
when we discuss “normal” values, it is with the under-
standing that many of the body’s control systems are con-
stantly reacting to perturbations, and that variability may
exist among different individuals, depending on body
weight and height, diet, age, sex, environment, genetics,
and other factors.
For simplicity, discussion of physiological functions
often focuses on the “average” 70-­kg young, lean male.
However, the American male no longer weighs an aver-
age of 70 kg; he now weighs over 88 kg, and the average
American female weighs over 76 kg, more than the aver-
age man in the 1960s. Body weight has also increased sub-
stantially in most other industrialized countries during
the past 40 to 50 years.
Except for reproductive and hormonal functions,
many other physiological functions and normal values
are often discussed in terms of male physiology. However,
there are clearly differences in male and female physiology
beyond the obvious differences that relate to reproduc-
tion. These differences can have important consequences
10
for understanding normal physiology as well as for treat-
ment of diseases.
Age-­related and ethnic or racial differences in physiol-
ogy also have important influences on body composition,
physiological control systems, and pathophysiology of
diseases. For example, in a lean young male the total body
water is about 60% of body weight. As a person grows and
ages, this percentage gradually decreases, partly because
aging is usually associated with declining skeletal muscle
mass and increasing fat mass. Aging may also cause a
decline in the function and effectiveness of some organs
and physiological control systems.
These sources of physiological variability—sex differ-
ences, aging, ethnic, and racial—are complex but impor-
tant considerations when discussing normal physiology
and the pathophysiology of diseases.
SUMMARY—AUTOMATICITY OF THE
BODY
The main purpose of this chapter has been to discuss
briefly the overall organization of the body and the means
whereby the different parts of the body operate in har-
mony. To summarize, the body is actually a social order of
about 35 to 40 trillion cells organized into different func-
tional structures, some of which are called organs. Each
functional structure contributes its share to the mainte-
nance of homeostasis in the extracellular fluid, which is
called the internal environment. As long as normal con-
ditions are maintained in this internal environment, the
cells of the body continue to live and function properly.
Each cell benefits from homeostasis and, in turn, each
cell contributes its share toward the maintenance of
homeostasis. This reciprocal interplay provides continu-
ous automaticity of the body until one or more functional
systems lose their ability to contribute their share of func-
tion. When this happens, all the cells of the body suffer.
Extreme dysfunction leads to death; moderate dysfunc-
tion leads to sickness.
Bibliography
Adolph EF: Physiological adaptations: hypertrophies and superfunc-
tions. Am Sci 60:608, 1972.
Bentsen MA, Mirzadeh Z, Schwartz MW: Revisiting how the brain
senses glucose-and why. Cell Metab 29:11, 2019.
Bernard C: Lectures on the Phenomena of Life Common to Animals
and Plants. Springfield, IL: Charles C Thomas, 1974.
Cannon WB: Organization for physiological homeostasis. Physiol Rev
9:399, 1929.
Chien S: Mechanotransduction and endothelial cell homeostasis: the
wisdom of the cell. Am J Physiol Heart Circ Physiol 292:H1209, 2007.
DiBona GF: Physiology in perspective: the wisdom of the body. Neu-
ral control of the kidney. Am J Physiol Regul Integr Comp Physiol
289:R633, 2005.
Dickinson MH, Farley CT, Full RJ, et al: How animals move: an integra-
tive view. Science 288:100, 2000.
Eckel-Mahan K, Sassone-Corsi P: Metabolism and the circadian clock
converge. Physiol Rev 93:107, 2013.
 Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment”
Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB
Saunders, 1980.
Herman MA, Kahn BB: Glucose transport and sensing in the mainte-
nance of glucose homeostasis and metabolic harmony. J Clin Invest
116:1767, 2006.
Kabashima K, Honda T, Ginhoux F, Egawa G: The immunological
anatomy of the skin. Nat Rev Immunol 19:19, 2019.
Khramtsova EA, Davis LK, Stranger BE: The role of sex in the genom-
ics of human complex traits. Nat Rev Genet 20: 173, 2019.
Kim KS, Seeley RJ, Sandoval DA: Signalling from the periphery to the
brain that regulates energy homeostasis. Nat Rev Neurosci 19:185,
2018.
Nishida AH, Ochman H: A great-ape view of the gut microbiome. Nat
Rev Genet 20:185, 2019.
Orgel LE: The origin of life on the earth. Sci Am 271:76,1994.
Reardon C, Murray K, Lomax AE: Neuroimmune communication in
health and disease. Physiol Rev 98:2287-2316, 2018.
Sender R, Fuchs S, Milo R: Revised estimates for the number of human
and bacteria cells in the body. PLoS Biol 14(8):e1002533, 2016.
UNIT I
Smith HW: From Fish to Philosopher. New York: Doubleday, 1961.
11

The Cell and Its Functions
Each of the trillions of cells in a human being is a living
structure that can survive for months or years, provided
its surrounding fluids contain appropriate nutrients. Cells
are the building blocks of the body, providing structure
for the body’s tissues and organs, ingesting nutrients and
converting them to energy, and performing specialized
functions. Cells also contain the body’s hereditary code,
which controls the substances synthesized by the cells
and permits them to make copies of themselves.
ORGANIZATION OF THE CELL
A schematic drawing of a typical cell, as seen by the light
microscope, is shown in Figure 2-1. Its two major parts
are the nucleus and the cytoplasm. The nucleus is sepa-
rated from the cytoplasm by a nuclear membrane, and the
cytoplasm is separated from the surrounding fluids by a
cell membrane, also called the plasma membrane.
The different substances that make up the cell are
collectively called protoplasm. Protoplasm is composed
mainly of five basic substances—water, electrolytes, pro-
teins, lipids, and carbohydrates.
Water. Most cells, except for fat cells, are comprised
mainly of water in a concentration of 70% to 85%. Many
cellular chemicals are dissolved in the water. Others are
suspended in the water as solid particulates. Chemical re-
actions take place among the dissolved chemicals or at the
surfaces of the suspended particles or membranes.
Ions. Important ions in the cell include potassium, magne-
sium, phosphate, sulfate, bicarbonate, and smaller quanti-
ties of sodium, chloride, and calcium. These ions are all
discussed in Chapter 4, which considers the interrelations
between the intracellular and extracellular fluids.
The ions provide inorganic chemicals for cellular reac-
tions and are necessary for the operation of some cellular
control mechanisms. For example, ions acting at the cell
membrane are required for the transmission of electro-
chemical impulses in nerve and muscle fibers.
Proteins. After water, the most abundant substances in
most cells are proteins, which normally constitute 10% to
CHAPTER 2
UNIT I
20% of the cell mass. These proteins can be divided into
two types, structural proteins and functional proteins.
Structural proteins are present in the cell mainly in the
form of long filaments that are polymers of many indi-
vidual protein molecules. A prominent use of such intra-
cellular filaments is to form microtubules, which provide
the cytoskeletons of cellular organelles such as cilia, nerve
axons, the mitotic spindles of cells undergoing mitosis,
and a tangled mass of thin filamentous tubules that hold
the parts of the cytoplasm and nucleoplasm together in
their respective compartments. Fibrillar proteins are
found outside the cell, especially in the collagen and elas-
tin fibers of connective tissue, and elsewhere, such as in
blood vessel walls, tendons, and ligaments.
The functional proteins are usually composed of com-
binations of a few molecules in tubular-­globular form.
These proteins are mainly the enzymes of the cell and, in
contrast to the fibrillar proteins, are often mobile in the
cell fluid. Also, many of them are adherent to membra-
nous structures inside the cell and catalyze specific intra-
cellular chemical reactions. For example, the chemical
reactions that split glucose into its component parts and
then combine these with oxygen to form carbon diox-
ide and water while simultaneously providing energy for
cellular function are all catalyzed by a series of protein
enzymes.
Lipids. Lipids are several types of substances that are
grouped together because of their common property of
being soluble in fat solvents. Especially important lipids
Cell
membrane
Cytoplasm
Nucleolus
Nucleoplasm
Nuclear
membrane Nucleus
Figure 2-1. Illustration of cell structures visible with a light microscope.
13
UNIT I Introduction to Physiology: The Cell and General Physiology
Centrioles
Secretory
granule
Microtubules
Nuclear
membrane
Mitochondrion Rough (granular)
endoplasmic
reticulum
Figure 2-2. Reconstruction of a typical cell, showing the internal organelles in the cytoplasm and nucleus.
are phospholipids and cholesterol, which together consti-
tute only about 2% of the total cell mass. Phospholipids
and cholesterol are mainly insoluble in water and there-
fore are used to form the cell membrane and intracellular
membrane barriers that separate the different cell com-
partments.
In addition to phospholipids and cholesterol, some
cells contain large quantities of triglycerides, also called
neutral fats. In fat cells (adipocytes), triglycerides often
account for as much as 95% of the cell mass. The fat stored
in these cells represents the body’s main storehouse of
energy-­giving nutrients that can later be used to provide
energy wherever it is needed in the body.
Carbohydrates. Carbohydrates play a major role in cell
nutrition and, as parts of glycoprotein molecules, have
structural functions. Most human cells do not maintain
large stores of carbohydrates; the amount usually averages
only about 1% of their total mass but increases to as much
as 3% in muscle cells and, occasionally, to 6% in liver cells.
However, carbohydrate in the form of dissolved glucose
is always present in the surrounding extracellular fluid so
14
Chromosomes and DNA
Golgi
apparatus
Cell
membrane
Nucleolus
Glycogen
Ribosomes
Lysosome
Smooth (agranular) Microfilaments
endoplasmic
reticulum
that it is readily available to the cell. Also, a small amount
of carbohydrate is stored in cells as glycogen, an insoluble
polymer of glucose that can be depolymerized and used
rapidly to supply the cell’s energy needs.
CELL STRUCTURE
The cell contains highly organized physical structures
called intracellular organelles, which are critical for cell
function. For example, without one of the organelles, the
mitochondria, more than 95% of the cell’s energy release
from nutrients would cease immediately. The most
important organelles and other structures of the cell are
shown in Figure 2-2.
MEMBRANOUS STRUCTURES OF THE CELL
Most organelles of the cell are covered by membranes
composed primarily of lipids and proteins. These mem-
branes include the cell membrane, nuclear membrane,
membrane of the endoplasmic reticulum, and membranes
of the mitochondria, lysosomes, and Golgi apparatus.

Extracellular
fluid
Integral protein
Integral protein
Figure 2-3. Structure of the cell membrane showing that it is composed mainly of a lipid bilayer of phospholipid molecules, but with large
numbers of protein molecules protruding through the layer. Also, carbohydrate moieties are attached to the protein molecules on the outside
of the membrane and to additional protein molecules on the inside.
The lipids in membranes provide a barrier that
impedes movement of water and water-­ soluble sub-
stances from one cell compartment to another because
water is not soluble in lipids. However, protein mole-
cules often penetrate all the way through membranes,
thus providing specialized pathways, often organized
into actual pores, for passage of specific substances
through membranes. Also, many other membrane
proteins are enzymes, which catalyze a multitude of
different chemical reactions, discussed here and in sub-
sequent chapters.
Cell Membrane
The cell membrane (also called the plasma membrane)
envelops the cell and is a thin, pliable, elastic structure
only 7.5 to 10 nanometers thick. It is composed almost
entirely of proteins and lipids. The approximate composi-
tion is 55% proteins, 25% phospholipids, 13% cholesterol,
4% other lipids, and 3% carbohydrates.
The Cell Membrane Lipid Barrier Impedes Penetra-
tion by Water-­Soluble Substances. Figure 2-3 shows
the structure of the cell membrane. Its basic structure
is a lipid bilayer, which is a thin, double-­layered film
of lipids—each layer only one molecule thick—that is
Chapter 2 The Cell and Its Functions
Carbohydrate
UNIT I
Lipid
bilayer
Peripheral
protein
Intracellular
fluid
Cytoplasm
c­ontinuous over the entire cell surface. Interspersed in
this lipid film are large globular proteins.
The basic lipid bilayer is composed of three main types
of lipids—phospholipids, sphingolipids, and cholesterol.
Phospholipids are the most abundant cell membrane
lipids. One end of each phospholipid molecule is hydro-
philic and soluble in water. The other end is hydropho-
bic and soluble only in fats. The phosphate end of the
phospholipid is hydrophilic, and the fatty acid portion is
hydrophobic.
Because the hydrophobic portions of the phospholipid
molecules are repelled by water but are mutually attracted
to one another, they have a natural tendency to attach to
one another in the middle of the membrane, as shown in
Figure 2-3. The hydrophilic phosphate portions then con-
stitute the two surfaces of the complete cell membrane, in
contact with intracellular water on the inside of the mem-
brane and extracellular water on the outside surface.
The lipid layer in the middle of the membrane is
impermeable to the usual water-­soluble substances, such
as ions, glucose, and urea. Conversely, fat-­soluble sub-
stances, such as oxygen, carbon dioxide, and alcohol, can
penetrate this portion of the membrane with ease.
Sphingolipids, derived from the amino alcohol sphin-
gosine, also have hydrophobic and hydrophilic groups and
15
UNIT I Introduction to Physiology: The Cell and General Physiology
are present in small amounts in the cell membranes, espe-
cially nerve cells. Complex sphingolipids in cell mem-
branes are thought to serve several functions, including
protection from harmful environmental factors, signal
transmission, and adhesion sites for extracellular proteins.
Cholesterol molecules in membranes are also lipids
because their steroid nuclei are highly fat-­soluble. These
molecules, in a sense, are dissolved in the bilayer of the
membrane. They mainly help determine the degree of
permeability (or impermeability) of the bilayer to water-­
soluble constituents of body fluids. Cholesterol controls
much of the fluidity of the membrane as well.
Integral and Peripheral Cell Membrane Proteins.
Figure 2-3 also shows globular masses floating in the
lipid bilayer. These membrane proteins are mainly glyco-
proteins. There are two types of cell membrane proteins,
integral proteins, which protrude all the way through
the membrane, and peripheral proteins, which are
attached only to one surface of the membrane and do
not penetrate all the way through.
Many of the integral proteins provide structural chan-
nels (or pores) through which water molecules and water-­
soluble substances, especially ions, can diffuse between
extracellular and intracellular fluids. These protein chan-
nels also have selective properties that allow preferential
diffusion of some substances over others.
Other integral proteins act as carrier proteins for trans-
porting substances that otherwise could not penetrate
the lipid bilayer. Sometimes, these carrier proteins even
transport substances in the direction opposite to their
electrochemical gradients for diffusion, which is called
active transport. Still others act as enzymes.
Integral membrane proteins can also serve as receptors
for water-­soluble chemicals, such as peptide hormones,
that do not easily penetrate the cell membrane. Interac-
tion of cell membrane receptors with specific ligands that
bind to the receptor causes conformational changes in
the receptor protein. This process, in turn, enzymatically
activates the intracellular part of the protein or induces
interactions between the receptor and proteins in the
cytoplasm that act as second messengers, relaying the sig-
nal from the extracellular part of the receptor to the inte-
rior of the cell. In this way, integral proteins spanning the
cell membrane provide a means of conveying information
about the environment to the cell interior.
Peripheral protein molecules are often attached to
integral proteins. These peripheral proteins function
almost entirely as enzymes or as controllers of transport
of substances through cell membrane pores.
Membrane Carbohydrates—The Cell “Glycocalyx.”
Membrane carbohydrates occur almost invariably in com-
bination with proteins or lipids in the form of glycopro-
teins or glycolipids. In fact, most of the integral proteins
are glycoproteins, and about one-tenth of the membrane
lipid molecules are glycolipids. The glyco-­ portions of
16
these molecules almost invariably protrude to the outside
of the cell, dangling outward from the cell surface. Many
other carbohydrate compounds, called proteoglycans—
which are mainly carbohydrates bound to small protein
cores—are loosely attached to the outer surface of the cell
as well. Thus, the entire outside surface of the cell often
has a loose carbohydrate coat called the glycocalyx.
The carbohydrate moieties attached to the outer sur-
face of the cell have several important functions:
1. Many of them have a negative electrical charge,
which gives most cells an overall negative surface
charge that repels other negatively charged objects.
2. The glycocalyx of some cells attaches to the glycoca-
lyx of other cells, thus attaching cells to one another.
3. Many of the carbohydrates act as receptors for bind-
ing hormones, such as insulin. When bound, this
combination activates attached internal proteins that
in turn activate a cascade of intracellular enzymes.
4. Some carbohydrate moieties enter into immune re-
actions, as discussed in Chapter 35.
CYTOPLASM AND ITS ORGANELLES
The cytoplasm is filled with minute and large dispersed
particles and organelles. The jelly-­like fluid portion of the
cytoplasm in which the particles are dispersed is called
cytosol and contains mainly dissolved proteins, electro-
lytes, and glucose.
Dispersed in the cytoplasm are neutral fat globules,
glycogen granules, ribosomes, secretory vesicles, and five
especially important organelles—the endoplasmic reticu-
lum, the Golgi apparatus, mitochondria, lysosomes, and
peroxisomes.
Endoplasmic Reticulum
Figure 2-2 shows the endoplasmic reticulum, a network
of tubular structures called cisternae and flat vesicular
structures in the cytoplasm. This organelle helps pro-
cess molecules made by the cell and transports them to
their specific destinations inside or outside the cell. The
tubules and vesicles interconnect. Also, their walls are
constructed of lipid bilayer membranes that contain large
amounts of proteins, similar to the cell membrane. The
total surface area of this structure in some cells—the liver
cells, for example—can be as much as 30 to 40 times the
cell membrane area.
The detailed structure of a small portion of endoplas-
mic reticulum is shown in Figure 2-4. The space inside
the tubules and vesicles is filled with endoplasmic matrix,
a watery medium that is different from fluid in the cytosol
outside the endoplasmic reticulum. Electron micrographs
show that the space inside the endoplasmic reticulum is
connected with the space between the two membrane
surfaces of the nuclear membrane.
Substances formed in some parts of the cell enter the
space of the endoplasmic reticulum and are then directed
to other parts of the cell. Also, the vast surface area of this

Ribosome
Matrix
Rough (granular)
endoplasmic
reticulum Smooth (agranular)
endoplasmic
reticulum
Figure 2-4. Structure of the endoplasmic reticulum.
reticulum and the multiple enzyme systems attached to
its membranes provide the mechanisms for a major share
of the cell’s metabolic functions.
Ribosomes and the Rough (Granular) Endoplasmic
Reticulum. Attached to the outer surfaces of many parts
of the endoplasmic reticulum are large numbers of minute
granular particles called ribosomes. Where these particles
are present, the reticulum is called the rough (granular)
endoplasmic reticulum. The ribosomes are composed of a
mixture of RNA and proteins; they function to synthesize
new protein molecules in the cell, as discussed later in this
chapter and in Chapter 3.
Smooth (Agranular) Endoplasmic Reticulum. Part of
the endoplasmic reticulum has no attached ribosomes.
This part is called the smooth, or agranular, endoplasmic
reticulum. The smooth reticulum functions for the syn-
thesis of lipid substances and for other processes of the
cells promoted by intrareticular enzymes.
Golgi Apparatus
The Golgi apparatus, shown in Figure 2-5, is closely
related to the endoplasmic reticulum. It has membranes
similar to those of the smooth endoplasmic reticulum.
The Golgi apparatus is usually composed of four or more
stacked layers of thin, flat, enclosed vesicles lying near one
side of the nucleus. This apparatus is prominent in secre-
tory cells, where it is located on the side of the cell from
which secretory substances are extruded.
The Golgi apparatus functions in association with the
endoplasmic reticulum. As shown in Figure 2-5, small
transport vesicles (also called endoplasmic reticulum
vesicles [ER vesicles]) continually pinch off from the endo-
plasmic reticulum and shortly thereafter fuse with the
Golgi apparatus. In this way, substances entrapped in ER
Chapter 2 The Cell and Its Functions
Golgi vesicles
Golgi
UNIT I
apparatus
ER vesicles
Endoplasmic
reticulum
Figure 2-5. A typical Golgi apparatus and its relationship to the
endoplasmic reticulum (ER) and the nucleus.
vesicles are transported from the endoplasmic reticulum
to the Golgi apparatus. The transported substances are
then processed in the Golgi apparatus to form lysosomes,
secretory vesicles, and other cytoplasmic components
(discussed later in this chapter).
Lysosomes
Lysosomes, shown in Figure 2-2, are vesicular organ-
elles that form by breaking off from the Golgi appara-
tus; they then disperse throughout the cytoplasm. The
lysosomes provide an intracellular digestive system that
allows the cell to digest the following: (1) damaged cellu-
lar structures; (2) food particles that have been ingested
by the cell; and (3) unwanted matter such as bacteria.
Lysosome are different in various cell types but are usu-
ally 250 to 750 nanometers in diameter. They are sur-
rounded by typical lipid bilayer membranes and are filled
with large numbers of small granules, 5 to 8 nanometers
in diameter, which are protein aggregates of as many as
40 different hydrolase (digestive) enzymes. A hydrolytic
enzyme is capable of splitting an organic compound into
two or more parts by combining hydrogen from a water
molecule with one part of the compound and combin-
ing the hydroxyl portion of the water molecule with the
other part of the compound. For example, protein is
hydrolyzed to form amino acids, glycogen is hydrolyzed
to form glucose, and lipids are hydrolyzed to form fatty
acids and glycerol.
Hydrolytic enzymes are highly concentrated in lyso-
somes. Ordinarily, the membrane surrounding the lyso-
some prevents the enclosed hydrolytic enzymes from
coming into contact with other substances in the cell and
therefore prevents their digestive actions. However, some
conditions of the cell break the membranes of lysosomes,
allowing release of the digestive enzymes. These enzymes
then split the organic substances with which they come
in contact into small, highly diffusible substances such as
17
UNIT I Introduction to Physiology: The Cell and General Physiology
Secretory
granules
Figure 2-6. Secretory granules (secretory vesicles) in acinar cells of
the pancreas.
amino acids and glucose. Some of the specific functions of
lysosomes are discussed later in this chapter.
Peroxisomes
Peroxisomes are physically similar to lysosomes, but
they are different in two important ways. First, they are
believed to be formed by self-­replication (or perhaps by
budding off from the smooth endoplasmic reticulum)
rather than from the Golgi apparatus. Second, they con-
tain oxidases rather than hydrolases. Several of the oxi-
dases are capable of combining oxygen with hydrogen
ions derived from different intracellular chemicals to
form hydrogen peroxide (H2O2). Hydrogen peroxide is a
highly oxidizing substance and is used in association with
catalase, another oxidase enzyme present in large quan-
tities in peroxisomes, to oxidize many substances that
might otherwise be poisonous to the cell. For example,
about half the alcohol that a person drinks is detoxified
into acetaldehyde by the peroxisomes of the liver cells in
this manner. A major function of peroxisomes is to catab-
olize long-­chain fatty acids.
Secretory Vesicles
One of the important functions of many cells is secretion
of special chemical substances. Almost all such secretory
substances are formed by the endoplasmic reticulum–
Golgi apparatus system and are then released from the
Golgi apparatus into the cytoplasm in the form of stor-
age vesicles called secretory vesicles or secretory granules.
Figure 2-6 shows typical secretory vesicles inside pancre-
atic acinar cells; these vesicles store protein proenzymes
(enzymes that are not yet activated). The proenzymes are
secreted later through the outer cell membrane into the
pancreatic duct and then into the duodenum, where they
become activated and perform digestive functions on the
food in the intestinal tract.
Mitochondria
The mitochondria, shown in Figure 2-2 and Figure 2-7,
are called the powerhouses of the cell. Without them, cells
would be unable to extract enough energy from the nutri-
ents, and essentially all cellular functions would cease.
18
Outer membrane
Inner membrane
Cristae Matrix
Oxidative
phosphorylation
Outer chamber enzymes
Figure 2-7. Structure of a mitochondrion.
Mitochondria are present in all areas of each cell’s
cytoplasm, but the total number per cell varies from less
than 100 up to several thousand, depending on the energy
requirements of the cell. Cardiac muscle cells (cardiomyo-
cytes), for example, use large amounts of energy and have
far more mitochondria than fat cells (adipocytes), which
are much less active and use less energy. Furthermore,
the mitochondria are concentrated in those portions
of the cell responsible for the major share of its energy
metabolism. They are also variable in size and shape.
Some mitochondria are only a few hundred nanometers
in diameter and are globular in shape, whereas others are
elongated and are as large as 1 micrometer in diameter
and 7 micrometers long. Still others are branching and
filamentous.
The basic structure of the mitochondrion, shown
in Figure 2-7, is composed mainly of two lipid bilayer-­
protein membranes, an outer membrane and an inner
membrane. Many infoldings of the inner membrane form
shelves or tubules called cristae onto which oxidative
enzymes are attached. The cristae provide a large surface
area for chemical reactions to occur. In addition, the inner
cavity of the mitochondrion is filled with a matrix that
contains large quantities of dissolved enzymes necessary
for extracting energy from nutrients. These enzymes oper-
ate in association with oxidative enzymes on the cristae
to cause oxidation of nutrients, thereby forming carbon
dioxide and water and, at the same time, releasing energy.
The liberated energy is used to synthesize a high-­energy
substance called adenosine triphosphate (ATP). ATP is
then transported out of the mitochondrion and diffuses
throughout the cell to release its own energy wherever it
is needed for performing cellular functions. The chemical
details of ATP formation by the mitochondrion are pro-
vided in Chapter 68, but some basic functions of ATP in
the cell are introduced later in this chapter.
Mitochondria are self-­replicative, which means that
one mitochondrion can form a second one, a third one,
and so on whenever the cell needs increased amounts
of ATP. Indeed, the mitochondria contain DNA similar
to that found in the cell nucleus. In Chapter 3, we will
see that DNA is the basic constituent of the nucleus that

Endoplasmic Ribosome Cell membrane
reticulum
Microtubule
Mitochondrion
Intermediate filament
Figure 2-8. Cell cytoskeleton composed of protein fibers called microfilaments, intermediate filaments, and microtubules.
controls replication of the cell. The DNA of the mitochon-
drion plays a similar role, controlling replication of the
mitochondrion. Cells that are faced with increased energy
demands—for example, in skeletal muscles subjected to
chronic exercise training—may increase the density of
mitochondria to supply the additional energy required.
Cell Cytoskeleton—Filament and Tubular
Structures
The cell cytoskeleton is a network of fibrillar proteins
organized into filaments or tubules. These originate as
precursor proteins synthesized by ribosomes in the cyto-
plasm. The precursor molecules then polymerize to form
filaments (Figure 2-8). As an example, large numbers of
actin microfilaments frequently occur in the outer zone
of the cytoplasm, called the ectoplasm, to form an elas-
tic support for the cell membrane. Also, in muscle cells,
actin and myosin filaments are organized into a special
contractile machine that is the basis for muscle contrac-
tion, as discussed in Chapter 6.
Intermediate filaments are generally strong ropelike
filaments that often work together with microtubules,
providing strength and support for the fragile tubulin
structures. They are called intermediate because their
average diameter is between that of narrower actin micro-
filaments and wider myosin filaments found in muscle
cells. Their functions are mainly mechanical, and they are
less dynamic than actin microfilaments or microtubules.
Chapter 2 The Cell and Its Functions
α-Tubulin β-Tubulin
monomer monomer
Microfilaments
Microtubule
(25 nm)
UNIT I
Fibrous protein
dimer
Intermediate
filament
(8-12 nm)
Microfilament
(7 nm)
Two intertwined
F-actin chains
G-actin
monomer
All cells have intermediate filaments, although the pro-
tein subunits of these structures vary, depending on the
cell type. Specific intermediate filaments found in various
cells include desmin filaments in muscle cells, neurofila-
ments in neurons, and keratins in epithelial cells.
A special type of stiff filament composed of polym-
erized tubulin molecules is used in all cells to construct
strong tubular structures, the microtubules. Figure 2-8
shows typical microtubules of a cell.
Another example of microtubules is the tubular skeletal
structure in the center of each cilium that radiates upward
from the cell cytoplasm to the tip of the cilium. This struc-
ture is discussed later in the chapter (see Figure 2-18). Also,
both the centrioles and mitotic spindles of cells undergoing
mitosis are composed of stiff microtubules.
A major function of microtubules is to act as a cyto-
skeleton, providing rigid physical structures for certain
parts of cells. The cell cytoskeleton not only determines
cell shape but also participates in cell division, allows cells
to move, and provides a tracklike system that directs the
movement of organelles in the cells. Microtubules serve
as the conveyor belts for the intracellular transport of
vesicles, granules, and organelles such as mitochondria.
Nucleus
The nucleus is the control center of the cell and sends
messages to the cell to grow and mature, replicate, or
die. Briefly, the nucleus contains large quantities of DNA,
19
UNIT I Introduction to Physiology: The Cell and General Physiology
Pores
Endoplasmic
reticulum
Nucleoplasm
Nucleolus
Nuclear envelope:
outer and inner
membranes
Chromatin material (DNA)
Cytoplasm
Figure 2-9. Structure of the nucleus.
which comprise the genes. The genes determine the char-
acteristics of the cell’s proteins, including the structural
proteins, as well as the intracellular enzymes that control
cytoplasmic and nuclear activities.
The genes also control and promote cell reproduction.
The genes first reproduce to create two identical sets of
genes; then the cell splits by a special process called mito-
sis to form two daughter cells, each of which receives one
of the two sets of DNA genes. All these activities of the
nucleus are discussed in Chapter 3.
Unfortunately, the appearance of the nucleus under the
microscope does not provide many clues to the mecha-
nisms whereby the nucleus performs its control activities.
Figure 2-9 shows the light microscopic appearance of the
interphase nucleus (during the period between mitoses),
revealing darkly staining chromatin material throughout
the nucleoplasm. During mitosis, the chromatin material
organizes in the form of highly structured chromosomes,
which can then be easily identified using the light micro-
scope, as illustrated in Chapter 3.
Nuclear Membrane. The nuclear membrane, also called
the nuclear envelope, is actually two separate bilayer
membranes, one inside the other. The outer membrane
is continuous with the endoplasmic reticulum of the cell
cytoplasm, and the space between the two nuclear mem-
branes is also continuous with the space inside the endo-
plasmic reticulum, as shown in Figure 2-9.
The nuclear membrane is penetrated by several thou-
sand nuclear pores. Large complexes of proteins are
attached at the edges of the pores so that the central area
of each pore is only about 9 nanometers in diameter.
Even this size is large enough to allow molecules up to a
molecular weight of 44,000 to pass through with reason-
able ease.
Nucleoli and Formation of Ribosomes. The nuclei of
most cells contain one or more highly staining structures
called nucleoli. The nucleolus, unlike most other orga-
nelles discussed here, does not have a limiting membrane.
Instead, it is simply an accumulation of large amounts of
20
15 nm: Small virus
150 nm: Large virus
350 nm: Rickettsia
1 µm Bacterium
Cell
5-10 µm+
Figure 2-10. Comparison of sizes of precellular organisms with that
of the average cell in the human body.
RNA and proteins of the types found in ribosomes. The
nucleolus enlarges considerably when the cell is actively
synthesizing proteins.
Formation of the nucleoli (and of the ribosomes in
the cytoplasm outside the nucleus) begins in the nucleus.
First, specific DNA genes in the chromosomes cause
RNA to be synthesized. Some of this synthesized RNA is
stored in the nucleoli, but most of it is transported out-
ward through the nuclear pores into the cytoplasm. Here
it is used in conjunction with specific proteins to assemble
“mature” ribosomes that play an essential role in forming
cytoplasmic proteins, as discussed in Chapter 3.
COMPARISON OF THE ANIMAL CELL
WITH PRECELLULAR FORMS OF LIFE
The cell is a complicated organism that required many
hundreds of millions of years to develop after the earli-
est forms of life, microorganisms that may have been
similar to present-­day viruses, first appeared on earth.
Figure 2-10 shows the relative sizes of the following: (1)
the smallest known virus; (2) a large virus; (3) a Rickett-
sia; (4) a bacterium; and (5) a nucleated cell, This dem-
onstrates that the cell has a diameter about 1000 times
that of the smallest virus and therefore a volume about 1
billion times that of the smallest virus. Correspondingly,
the functions and anatomical organization of the cell are
also far more complex than those of the virus.
The essential life-­giving constituent of the small virus is
a nucleic acid embedded in a coat of protein. This nucleic
acid is composed of the same basic nucleic acid constit-
uents (DNA or RNA) found in mammalian cells and is
capable of reproducing itself under appropriate condi-
tions. Thus, the virus propagates its lineage from genera-
tion to generation and is therefore a living structure in the
same way that cells and humans are living structures.
As life evolved, other chemicals in addition to nucleic
acid and simple proteins became integral parts of the
organism, and specialized functions began to develop
in different parts of the virus. A membrane formed

around the virus and, inside the membrane, a fluid matrix
appeared. Specialized chemicals then developed inside
the fluid to perform special functions; many protein
enzymes appeared that were capable of catalyzing chemi-
cal reactions, thus determining the organism’s activities.
In still later stages of life, particularly in the rickett-
sial and bacterial stages, organelles developed inside the
organism. These represent physical structures of chemi-
cal aggregates that perform functions in a more efficient
manner than what can be achieved by dispersed chemi-
cals throughout the fluid matrix.
Finally, in the nucleated cell, still more complex organ-
elles developed, the most important of which is the
nucleus. The nucleus distinguishes this type of cell from
all lower forms of life; it provides a control center for all
cellular activities and for reproduction of new cells gen-
eration after generation, with each new cell having almost
exactly the same structure as its progenitor.
FUNCTIONAL SYSTEMS OF THE CELL
In the remainder of this chapter, we discuss some func-
tional systems of the cell that make it a living organism.
ENDOCYTOSIS—INGESTION BY THE CELL
If a cell is to live and grow and reproduce, it must obtain
nutrients and other substances from the surrounding flu-
ids. Most substances pass through the cell membrane by
the processes of diffusion and active transport.
Diffusion involves simple movement through the mem-
brane caused by the random motion of the molecules of
the substance. Substances move through cell membrane
pores or, in the case of lipid-­soluble substances, through
the lipid matrix of the membrane.
Active transport involves actually carrying a substance
through the membrane by a physical protein structure
that penetrates all the way through the membrane. These
active transport mechanisms are so important to cell
function that they are presented in detail in Chapter 4.
Large particles enter the cell by a specialized func-
tion of the cell membrane called endocytosis (Video 2-­1).
The principal forms of endocytosis are pinocytosis and
phagocytosis. Pinocytosis means the ingestion of minute
particles that form vesicles of extracellular fluid and par-
ticulate constituents inside the cell cytoplasm. Phagocyto-
sis means the ingestion of large particles, such as bacteria,
whole cells, or portions of degenerating tissue.
Pinocytosis. Pinocytosis occurs continually in the cell
membranes of most cells, but is especially rapid in some
cells. For example, it occurs so rapidly in macrophages
that about 3% of the total macrophage membrane is en-
gulfed in the form of vesicles each minute. Even so, the
pinocytotic vesicles are so small—usually only 100 to 200
nanometers in diameter—that most of them can be seen
only with an electron microscope.
Chapter 2 The Cell and Its Functions
Proteins Receptors
Coated pit
Clathrin
UNIT I
A B
Actin and myosin Dissolving clathrin
C D
Figure 2-11. Mechanism of pinocytosis.
Pinocytosis is the only means whereby most large
macromolecules, such as most proteins, can enter cells.
In fact, the rate at which pinocytotic vesicles form is usu-
ally enhanced when such macromolecules attach to the
cell membrane.
Figure 2-11 demonstrates the successive steps of
pinocytosis (A–D), showing three molecules of protein
attaching to the membrane. These molecules usually
attach to specialized protein receptors on the surface of
the membrane that are specific for the type of protein
that is to be absorbed. The receptors generally are con-
centrated in small pits on the outer surface of the cell
membrane, called coated pits. On the inside of the cell
membrane beneath these pits is a latticework of fibrillar
protein called clathrin, as well as other proteins, perhaps
including contractile filaments of actin and myosin. Once
the protein molecules have bound with the receptors, the
surface properties of the local membrane change in such
a way that the entire pit invaginates inward, and fibrillar
proteins surrounding the invaginating pit cause its bor-
ders to close over the attached proteins, as well as over a
small amount of extracellular fluid. Immediately thereaf-
ter, the invaginated portion of the membrane breaks away
from the surface of the cell, forming a pinocytotic vesicle
inside the cytoplasm of the cell.
What causes the cell membrane to go through the
necessary contortions to form pinocytotic vesicles is still
unclear. This process requires energy from within the cell,
which is supplied by ATP, a high-­energy substance dis-
cussed later in this chapter. This process also requires the
presence of calcium ions in the extracellular fluid, which
probably react with contractile protein filaments beneath
the coated pits to provide the force for pinching the vesi-
cles away from the cell membrane.
Phagocytosis. Phagocytosis occurs in much the same
way as pinocytosis, except that it involves large particles
rather than molecules. Only certain cells have the capa-
bility of phagocytosis—notably, tissue macrophages and
some white blood cells.
21
UNIT I Introduction to Physiology: The Cell and General Physiology
Lysosomes
Pinocytotic or
phagocytic
vesicle
Digestive vesicle
Residual body
Excretion
Figure 2-12. Digestion of substances in pinocytotic or phagocytic
vesicles by enzymes derived from lysosomes.
Phagocytosis is initiated when a particle such as a bac-
terium, dead cell, or tissue debris binds with receptors
on the surface of the phagocyte. In the case of bacteria,
each bacterium is usually already attached to a specific
antibody; it is the antibody that attaches to the phago-
cyte receptors, dragging the bacterium along with it. This
intermediation of antibodies is called opsonization, which
is discussed in Chapters 34 and 35.
Phagocytosis occurs in the following steps:
1. The cell membrane receptors attach to the surface
ligands of the particle.
2. The edges of the membrane around the points of
attachment evaginate outward within a fraction of
a second to surround the entire particle; then, pro-
gressively more and more membrane receptors at-
tach to the particle ligands. All this occurs suddenly
in a zipper-­like manner to form a closed phagocytic
vesicle.
3. Actin and other contractile fibrils in the cytoplasm
surround the phagocytic vesicle and contract
around its outer edge, pushing the vesicle to the in-
terior.
4. The contractile proteins then pinch the stem of the
vesicle so completely that the vesicle separates from
the cell membrane, leaving the vesicle in the cell in-
terior in the same way that pinocytotic vesicles are
formed.
LYSOSOMES DIGEST PINOCYTOTIC AND
PHAGOCYTIC FOREIGN SUBSTANCES
INSIDE THE CELL
Almost immediately after a pinocytotic or phagocytic ves-
icle appears inside a cell, one or more lysosomes become
attached to the vesicle and empty their acid hydrolases to
the inside of the vesicle, as shown in Figure 2-12. Thus,
a digestive vesicle is formed inside the cell cytoplasm in
which the vesicular hydrolases begin hydrolyzing the
22
proteins, carbohydrates, lipids, and other substances in the
vesicle. The products of digestion are small molecules of
substances such as amino acids, glucose, and phosphates
that can diffuse through the membrane of the vesicle into
the cytoplasm. What is left of the digestive vesicle, called
the residual body, represents indigestible substances. In
most cases, the residual body is finally excreted through
the cell membrane by a process called exocytosis, which is
essentially the opposite of endocytosis. Thus, the pinocy-
totic and phagocytic vesicles containing lysosomes can be
called the digestive organs of the cells.
Lysosomes and Regression of Tissues and Autolysis
of Damaged Cells. Tissues of the body often regress to
a smaller size. For example, this regression occurs in the
uterus after pregnancy, in muscles during long periods of
inactivity, and in mammary glands at the end of lactation.
Lysosomes are responsible for much of this regression.
Another special role of the lysosomes is the removal
of damaged cells or damaged portions of cells from tis-
sues. Damage to the cell—caused by heat, cold, trauma,
chemicals, or any other factor—induces lysosomes to
rupture. The released hydrolases immediately begin to
digest the surrounding organic substances. If the damage
is slight, only a portion of the cell is removed, and the cell
is then repaired. If the damage is severe, the entire cell is
digested, a process called autolysis. In this way, the cell is
completely removed, and a new cell of the same type is
formed, ordinarily by mitotic reproduction of an adjacent
cell to take the place of the old one.
The lysosomes also contain bactericidal agents that can
kill phagocytized bacteria before they cause cellular dam-
age. These agents include the following: (1) lysozyme, which
dissolves the bacterial cell wall; (2) lysoferrin, which binds
iron and other substances before they can promote bacterial
growth; and (3) acid at a pH of about 5.0, which activates the
hydrolases and inactivates bacterial metabolic systems.
Autophagy and Recycling of Cell Organelles.
Lysosomes play a key role in the process of autophagy,
which literally means “to eat oneself.” Autophagy is
a housekeeping process whereby obsolete organelles
and large protein aggregates are degraded and re-
cycled (Figure 2-13). Worn-­o ut cell organelles are
transferred to lysosomes by double-­m embrane struc-
tures called autophagosomes, which are formed in the
cytosol. Invagination of the lysosomal membrane and
the formation of vesicles provides another pathway for
cytosolic structures to be transported into the lumen
of lysosomes. Once inside the lysosomes, the orga-
nelles are digested, and the nutrients are reused by the
cell. Autophagy contributes to the routine turnover of
cytoplasmic components; it is a key mechanism for
tissue development, cell survival when nutrients are
scarce, and maintenance of homeostasis. In liver cells,
for example, the average mitochondrion normally has
a life span of only about 10 days before it is destroyed.

Isolation membrane
VESICLE
NUCLEATION
AUTOSOME
FORMATION
Autophagosome
Lysosome
DOCKING AND
FUSION WITH Autolysosome
LYSOSOME
Lysosomal
hydrolase
VESICLE BREAKDOWN AND DEGRADATION
Figure 2-13. Schematic diagram of autophagy steps.
SYNTHESIS OF CELLULAR STRUCTURES BY
ENDOPLASMIC RETICULUM AND GOLGI
APPARATUS
Endoplasmic Reticulum Functions
The extensiveness of the endoplasmic reticulum and Golgi
apparatus in secretory cells has already been emphasized.
These structures are formed primarily of lipid bilayer
membranes, similar to the cell membrane, and their walls
are loaded with protein enzymes that catalyze the synthe-
sis of many substances required by the cell.
Most synthesis begins in the endoplasmic reticulum.
The products formed there are then passed on to the Golgi
apparatus, where they are further processed before being
released into the cytoplasm. First, however, let us note the
specific products that are synthesized in specific portions
of the endoplasmic reticulum and Golgi apparatus.
Chapter 2 The Cell and Its Functions
Proteins Synthesis by the Rough Endoplasmic Reticu-
lum. The rough endoplasmic reticulum is characterized by
large numbers of ribosomes attached to the outer surfaces
of the endoplasmic reticulum membrane. As discussed in
Chapter 3, protein molecules are synthesized within the
structures of the ribosomes. The ribosomes extrude some
UNIT I
of the synthesized protein molecules directly into the cy-
tosol, but they also extrude many more through the wall
of the endoplasmic reticulum to the interior of the endo-
plasmic vesicles and tubules into the endoplasmic matrix.
Lipid Synthesis by the Smooth Endoplasmic Reticu-
lum. The endoplasmic reticulum also synthesizes lipids,
especially phospholipids and cholesterol. These lipids are
rapidly incorporated into the lipid bilayer of the endoplas-
mic reticulum, thus causing the endoplasmic reticulum to
grow more extensive. This process occurs mainly in the
smooth portion of the endoplasmic reticulum.
To keep the endoplasmic reticulum from growing
beyond the needs of the cell, small vesicles called ER
vesicles or transport vesicles continually break away from
the smooth reticulum; most of these vesicles then migrate
rapidly to the Golgi apparatus.
Other Functions of the Endoplasmic Reticulum.
Other significant functions of the endoplasmic reticu-
lum, especially the smooth reticulum, include the fol-
lowing:
1. It provides the enzymes that control glycogen
breakdown when glycogen is to be used for energy.
2. It provides a vast number of enzymes that are ca-
pable of detoxifying substances, such as drugs, that
might damage the cell. It achieves detoxification by
processes such as coagulation, oxidation, hydroly-
sis, and conjugation with glycuronic acid.
Golgi Apparatus Functions
Synthetic Functions of the Golgi Apparatus. Although
a major function of the Golgi apparatus is to provide ad-
ditional processing of substances already formed in the
endoplasmic reticulum, it can also synthesize certain
carbohydrates that cannot be formed in the endoplas-
mic reticulum. This is especially true for the formation of
large saccharide polymers bound with small amounts of
protein; important examples include hyaluronic acid and
chondroitin sulfate.
A few of the many functions of hyaluronic acid and
chondroitin sulfate in the body are as follows: (1) they
are the major components of proteoglycans secreted in
mucus and other glandular secretions; (2) they are the
major components of the ground substance, or nonfibrous
components of the extracellular matrix, outside the cells
in the interstitial spaces, which act as fillers between col-
lagen fibers and cells; (3) they are principal components of
the organic matrix in both cartilage and bone; and (4) they
are important in many cell activities, including migration
and proliferation.
23
UNIT I Introduction to Physiology: The Cell and General Physiology
Protein Lipid
Ribosomes formation formation Lysosomes
Transport
Glycosylation vesicles
Rough Smooth Golgi
endoplasmic endoplasmic apparatus
reticulum reticulum
Figure 2-14. Formation of proteins, lipids, and cellular vesicles by the
endoplasmic reticulum and Golgi apparatus.
Processing of Endoplasmic Secretions by the Golgi
Apparatus—Formation of Vesicles. Figure 2-14 sum-
marizes the major functions of the endoplasmic reticu-
lum and Golgi apparatus. As substances are formed in
the endoplasmic reticulum, especially proteins, they are
transported through the tubules toward portions of the
smooth endoplasmic reticulum that lie nearest to the
Golgi apparatus. At this point, transport vesicles com-
posed of small envelopes of smooth endoplasmic retic-
ulum continually break away and diffuse to the deepest
layer of the Golgi apparatus. Inside these vesicles are
synthesized proteins and other products from the endo-
plasmic reticulum.
The transport vesicles instantly fuse with the Golgi
apparatus and empty their contained substances into
the vesicular spaces of the Golgi apparatus. Here,
additional carbohydrate moieties are added to the
secretions. Also, an important function of the Golgi
apparatus is to compact the endoplasmic reticular
secretions into highly concentrated packets. As the
secretions pass toward the outermost layers of the
Golgi apparatus, the compaction and processing pro-
ceed. Finally, both small and large vesicles continually
break away from the Golgi apparatus, carrying with
them the compacted secretory substances and diffus-
ing throughout the cell.
The following example provides an idea of the tim-
ing of these processes. When a glandular cell is bathed
in amino acids, newly formed protein molecules can be
detected in the granular endoplasmic reticulum within 3
to 5 minutes. Within 20 minutes, newly formed proteins
are already present in the Golgi apparatus and, within 1
to 2 hours, the proteins are secreted from the surface of
the cell.
24
Secretory Types of Vesicles Formed by the Golgi Apparatus—
vesicles Secretory Vesicles and Lysosomes. In a highly secre-
tory cell, the vesicles formed by the Golgi apparatus are
mainly secretory vesicles containing proteins that are se-
creted through the surface of the cell membrane. These
secretory vesicles first diffuse to the cell membrane and
then fuse with it and empty their substances to the exte-
rior by the mechanism called exocytosis. Exocytosis, in
most cases, is stimulated by entry of calcium ions into
the cell. Calcium ions interact with the vesicular mem-
brane and cause its fusion with the cell membrane, fol-
lowed by exocytosis—opening of the membrane’s outer
surface and extrusion of its contents outside the cell.
Some vesicles, however, are destined for intracellular
use.
Use of Intracellular Vesicles to Replenish Cellular
Membranes. Some intracellular vesicles formed by the
Golgi apparatus fuse with the cell membrane or with the
membranes of intracellular structures such as the mito-
chondria and even the endoplasmic reticulum. This fusion
increases the expanse of these membranes and replenish-
es the membranes as they are used up. For example, the
cell membrane loses much of its substance every time it
forms a phagocytic or pinocytotic vesicle, and the vesicu-
lar membranes of the Golgi apparatus continually replen-
ish the cell membrane.
In summary, the membranous system of the endo-
plasmic reticulum and Golgi apparatus are highly
metabolic and capable of forming new intracellular
structures and secretory substances to be extruded
from the cell.
THE MITOCHONDRIA EXTRACT ENERGY
FROM NUTRIENTS
The principal substances from which cells extract energy
are foods that react chemically with oxygen—carbo-
hydrates, fats, and proteins. In the human body, essen-
tially all carbohydrates are converted into glucose by the
digestive tract and liver before they reach the other cells
of the body. Similarly, proteins are converted into amino
acids, and fats are converted into fatty acids. Figure 2-15
shows oxygen and the foodstuffs—glucose, fatty acids,
and amino acids—all entering the cell. Inside the cell,
they react chemically with oxygen under the influence
of enzymes that control the reactions and channel the
energy released in the proper direction. The details of all
these digestive and metabolic functions are provided in
Chapters 63 through 73.
Briefly, almost all these oxidative reactions occur
inside the mitochondria, and the energy that is released
is used to form the high-­energy compound ATP. Then,
ATP, not the original food, is used throughout the cell to
energize almost all the subsequent intracellular metabolic
reactions.
 Chapter 2 The Cell and Its Functions

the cell’s other functions, such as syntheses of substances

2ADP 2ATP and muscular contraction.
To reconstitute the cellular ATP as it is used up, energy
Glucose Gl
36 ADP derived from the cellular nutrients causes ADP and phos-
Fatty acids FA
phoric acid to recombine to form new ATP, and the entire
Amino acids AA Pyruvic acid process is repeated over and over. For these reasons, ATP

UNIT I
Acetoacetic has been called the energy currency of the cell because it
acid can be spent and reformed continually, having a turnover
Acetyl-CoA time of only a few minutes.
O2 O2 O2 ADP
CO2 CO2 CO2 + H2O ATP Chemical Processes in the Formation of ATP—Role
of the Mitochondria. On entry into the cells, glucose is
converted by enzymes in the cytoplasm into pyruvic acid
H2O H2O 36 ATP (a process called glycolysis). A small amount of ADP is
changed into ATP by the energy released during this con-
Mitochondrion
version, but this amount accounts for less than 5% of the
Cell membrane Cytoplasm overall energy metabolism of the cell.
About 95% of the cell’s ATP formation occurs in the
Figure 2-15. Formation of adenosine triphosphate (ATP) in the cell mitochondria. The pyruvic acid derived from carbo-
showing that most of the ATP is formed in the mitochondria. (ADP,
Adenosine diphosphate; CoA, coenzyme A.)
hydrates, fatty acids from lipids, and amino acids from
proteins is eventually converted into the compound
acetyl-­coenzyme A (CoA) in the matrix of mitochondria.
Functional Characteristics of Adenosine This substance, in turn, is further dissolved (for the pur-
Triphosphate pose of extracting its energy) by another series of enzymes
NH2 in the mitochondrion matrix, undergoing dissolution in a
sequence of chemical reactions called the citric acid cycle,
N C or Krebs cycle. These chemical reactions are so important
C N
HC Adenine that they are explained in detail in Chapter 68.
C CH In this citric acid cycle, acetyl-­CoA is split into its
N N O O O
component parts, hydrogen atoms and carbon dioxide.
O CH2 O P O~P O~P O– The carbon dioxide diffuses out of the mitochondria and
eventually out of the cell; finally, it is excreted from the
C H H C O– O– O–
body through the lungs.
Phosphate
H C C H The hydrogen atoms, conversely, are highly reactive;
they combine with oxygen that has also diffused into
OH OH
the mitochondria. This combination releases a tremen-
Ribose dous amount of energy, which is used by mitochondria
Adenosine triphosphate to convert large amounts of ADP to ATP. The processes
of these reactions are complex, requiring the participa-
ATP is a nucleotide composed of the following: (1) the tion of many protein enzymes that are integral parts of
nitrogenous base adenine; (2) the pentose sugar ribose; mitochondrial membranous shelves that protrude into the
and (3) three phosphate radicals. The last two phosphate mitochondrial matrix. The initial event is the removal of
radicals are connected with the remainder of the mol- an electron from the hydrogen atom, thus converting it to
ecule by high-­energy phosphate bonds, which are rep- a hydrogen ion. The terminal event is the combination of
resented in the formula shown by the symbol ∼. Under hydrogen ions with oxygen to form water and the release
the physical and chemical conditions of the body, each of of large amounts of energy to globular proteins that pro-
these high-­energy bonds contains about 12,000 calories trude like knobs from the membranes of the mitochon-
of energy per mole of ATP, which is many times greater drial shelves; these proteins are called ATP synthetase.
than the energy stored in the average chemical bond, thus Finally, the enzyme ATP synthetase uses the energy from
giving rise to the term high-­energy bond. Furthermore, the the hydrogen ions to convert ADP to ATP. The newly
high-­energy phosphate bond is very labile, so that it can formed ATP is transported out of the mitochondria into
be split instantly on demand whenever energy is required all parts of the cell cytoplasm and nucleoplasm, where it
to promote other intracellular reactions. energizes multiple cell functions.
When ATP releases its energy, a phosphoric acid This overall process for formation of ATP is called the
radical is split away, and adenosine diphosphate (ADP) is chemiosmotic mechanism of ATP formation. The chemi-
formed. This released energy is used to energize many of cal and physical details of this mechanism are presented

25
UNIT I Introduction to Physiology: The Cell and General Physiology
Ribosomes
Membrane
transport Endoplasmic
reticulum
Protein synthesis
Na+ Na+ ATP ADP
ADP
Mitochondrion
ATP ATP ADP
ATP ADP
Muscle contraction
Figure 2-16. Use of adenosine triphosphate (ATP; formed in the mi-
tochondrion) to provide energy for three major cellular functions—
membrane transport, protein synthesis, and muscle contraction.
(ADP, Adenosine diphosphate.)
in Chapter 68, and many of the detailed metabolic func-
tions of ATP in the body are discussed in Chapters 68
through 72.
Uses of ATP for Cellular Function. Energy from ATP
is used to promote three major categories of cellular
functions: (1) transport of substances through multiple
cell membranes; (2) synthesis of chemical compounds
throughout the cell; and (3) mechanical work. These uses
of ATP are illustrated by the examples in Figure 2-16:
(1) to supply energy for the transport of sodium through
the cell membrane; (2) to promote protein synthesis by
the ribosomes; and (3) to supply the energy needed dur-
ing muscle contraction.
In addition to the membrane transport of sodium,
energy from ATP is required for the membrane transport
of potassium, calcium, magnesium, phosphate, chloride,
urate, and hydrogen ions and many other ions, as well
as various organic substances. Membrane transport is
so important to cell function that some cells—the renal
tubular cells, for example—use as much as 80% of the
ATP that they form for this purpose alone.
In addition to synthesizing proteins, cells make phos-
pholipids, cholesterol, purines, pyrimidines, and many
other substances. Synthesis of almost any chemical com-
pound requires energy. For example, a single protein mol-
ecule might be composed of as many as several thousand
amino acids attached to one another by peptide linkages.
The formation of each of these linkages requires energy
derived from the breakdown of four high-­energy bonds;
thus, many thousand ATP molecules must release their
energy as each protein molecule is formed. Indeed, some
cells use as much as 75% of all the ATP formed in the cell
26
Movement of cell
Endocytosis
Pseudopodium
Exocytosis
Surrounding tissue Receptor binding
Figure 2-17. Ameboid motion by a cell.
simply to synthesize new chemical compounds, especially
protein molecules; this is particularly true during the
growth phase of cells.
Another use of ATP is to supply energy for special
cells to perform mechanical work. We discuss in Chap-
ter 6 that each contraction of a muscle fiber requires the
expenditure of large quantities of ATP energy. Other cells
perform mechanical work in other ways, especially by cili-
ary and ameboid motion, described later in this chapter.
The source of energy for all these types of mechanical
work is ATP.
In summary, ATP is readily available to release its
energy rapidly wherever it is needed in the cell. To replace
ATP used by the cell, much slower chemical reactions
break down carbohydrates, fats, and proteins and use the
energy derived from these processes to form new ATP.
More than 95% of this ATP is formed in the mitochon-
dria, which is why the mitochondria are called the power-
houses of the cell.
LOCOMOTION OF CELLS
The most obvious type of movement in the body is that
which occurs in skeletal, cardiac, and smooth muscle cells,
which constitute almost 50% of the entire body mass. The
specialized functions of these cells are discussed in Chapters
6 through 9. Two other types of movement—ameboid loco-
motion and ciliary movement—occur in other cells.
AMEBOID MOVEMENT
Ameboid movement is a crawling-­like movement of an
entire cell in relation to its surroundings, such as move-
ment of white blood cells through tissues. This type of
movement gets its name from the fact that amebae move
in this manner, and amebae have provided an excellent
tool for studying the phenomenon.
Typically, ameboid locomotion begins with the protru-
sion of a pseudopodium from one end of the cell. The pseu-
dopodium projects away from the cell body and partially
secures itself in a new tissue area; then the remainder of
the cell is pulled toward the pseudopodium. Figure 2-17

demonstrates this process, showing an elongated cell, the
right-­hand end of which is a protruding pseudopodium.
The membrane of this end of the cell is continually mov-
ing forward, and the membrane at the left-­hand end of the
cell is continually following along as the cell moves.
Mechanism of Ameboid Locomotion. Figure 2-17
shows the general principle of ameboid motion. Basical-
ly, this results from the continual formation of new cell
membrane at the leading edge of the pseudopodium and
continual absorption of the membrane in the mid and rear
portions of the cell. Two other effects are also essential for
forward movement of the cell. The first is attachment of
the pseudopodium to surrounding tissues so that it be-
comes fixed in its leading position while the remainder
of the cell body is being pulled forward toward the point
of attachment. This attachment is caused by receptor pro-
teins that line the insides of exocytotic vesicles. When the
vesicles become part of the pseudopodial membrane, they
open so that their insides evert to the outside, and the re-
ceptors now protrude to the outside and attach to ligands
in the surrounding tissues.
At the opposite end of the cell, the receptors pull away
from their ligands and form new endocytotic vesicles.
Then, inside the cell, these vesicles stream toward the
pseudopodial end of the cell, where they are used to form
new membrane for the pseudopodium.
The second essential effect for locomotion is to provide
the energy required to pull the cell body in the direction
of the pseudopodium. A moderate to large amount of the
protein actin is in the cytoplasm of all cells. Much of the
actin is in the form of single molecules that do not provide
any motive power; however, these molecules polymerize
to form a filamentous network, and the network contracts
when it binds with an actin-­binding protein such as myosin.
The entire process is energized by the high-­energy com-
pound ATP. This is what occurs in the pseudopodium of a
moving cell, where such a network of actin filaments forms
anew inside the enlarging pseudopodium. Contraction also
occurs in the ectoplasm of the cell body, where a preexisting
actin network is already present beneath the cell membrane.
Types of Cells That Exhibit Ameboid Locomotion.
The most common cells to exhibit ameboid locomotion
in the human body are the white blood cells when they
move out of the blood into the tissues to form tissue mac-
rophages. Other types of cells can also move by ameboid
locomotion under certain circumstances. For example,
fibroblasts move into a damaged area to help repair the
damage, and even the germinal cells of the skin, although
ordinarily completely sessile cells, move toward a cut area
to repair the opening. Cell locomotion is also especially
important in the development of the embryo and fetus
after fertilization of an ovum. For example, embryonic
cells often must migrate long distances from their sites
of origin to new areas during the development of special
structures.
Chapter 2 The Cell and Its Functions
Some types of cancer cells, such as sarcomas, which
arise from connective tissue cells, are especially proficient
at ameboid movement. This partially accounts for their
relatively rapid spreading from one part of the body to
another, known as metastasis.
UNIT I
Control of Ameboid Locomotion—Chemotaxis. An
important initiator of ameboid locomotion is the process
called chemotaxis, which results from the appearance of
certain chemical substances in the tissues. Any chemi-
cal substance that causes chemotaxis to occur is called
a chemotactic substance. Most cells that exhibit ameboid
locomotion move toward the source of a chemotactic
substance—that is, from an area of lower concentration
toward an area of higher concentration. This is called pos-
itive chemotaxis. Some cells move away from the source,
which is called negative chemotaxis.
How does chemotaxis control the direction of ame-
boid locomotion? Although the answer is not certain,
it is known that the side of the cell most exposed to the
chemotactic substance develops membrane changes that
cause pseudopodial protrusion.
CILIA AND CILIARY MOVEMENTS
There are two types of cilia, motile and nonmotile, or pri-
mary, cilia. Motile cilia can undergo a whiplike movement
on the surfaces of cells. This movement occurs mainly
in two places in the human body, on the surfaces of the
respiratory airways and on the inside surfaces of the uter-
ine tubes (fallopian tubes) of the reproductive tract. In the
nasal cavity and lower respiratory airways, the whiplike
motion of motile cilia causes a layer of mucus to move at
a rate of about 1 cm/min toward the pharynx, in this way
continually clearing these passageways of mucus and parti-
cles that have become trapped in the mucus. In the uterine
tubes, cilia cause slow movement of fluid from the ostium
of the uterine tube toward the uterus cavity; this movement
of fluid transports the ovum from the ovary to the uterus.
As shown in Figure 2-18, a cilium has the appearance
of a sharp-­pointed straight or curved hair that projects
2 to 4 micrometers from the surface of the cell. Often,
many motile cilia project from a single cell—for example,
as many as 200 cilia on the surface of each epithelial cell
inside the respiratory passageways. The cilium is covered
by an outcropping of the cell membrane, and it is sup-
ported by 11 microtubules—nine double tubules located
around the periphery of the cilium and two single tubules
down the center, as demonstrated in the cross section
shown in Figure 2-18. Each cilium is an outgrowth of
a structure that lies immediately beneath the cell mem-
brane, called the basal body of the cilium.
The flagellum of a sperm is similar to a motile cilium;
in fact, it has much the same type of structure and same
type of contractile mechanism. The flagellum, however, is
much longer and moves in quasisinusoidal waves instead
of whiplike movements.
27
UNIT I Introduction to Physiology: The Cell and General Physiology
Tip
Membrane
Cross section
Ciliary stalk
Filament
Forward stroke
Basal plate
Cell
membrane
Backward stroke
Basal body
Rootlet
Figure 2-18. Structure and function of the cilium. (Modified from
Satir P: Cilia. Sci Am 204:108, 1961.)
In the inset of Figure 2-18, movement of the motile
cilium is shown. The cilium moves forward with a sudden,
rapid whiplike stroke 10 to 20 times per second, bending
sharply where it projects from the surface of the cell. Then
it moves backward slowly to its initial position. The rapid,
forward-­thrusting, whiplike movement pushes the fluid
lying adjacent to the cell in the direction that the cilium
moves; the slow dragging movement in the backward
direction has almost no effect on fluid movement. As a
result, the fluid is continually propelled in the direction of
the fast-­forward stroke. Because most motile ciliated cells
have large numbers of cilia on their surfaces, and because
all the cilia are oriented in the same direction, this is an
effective means for moving fluids from one part of the
surface to another.
Mechanism of Ciliary Movement. Although not all
aspects of ciliary movement are known, we are aware
of the following elements. First, the nine double tubules
and two single tubules are all linked to one another by a
complex of protein cross-­linkages; this total complex of
tubules and cross-­linkages is called the axoneme. Second,
even after removal of the membrane and destruction of
other elements of the cilium in addition to the axoneme,
28
the cilium can still beat under appropriate conditions.
Third, two conditions are necessary for continued beating
of the axoneme after removal of the other structures of
the cilium: (1) the availability of ATP; and (2) appropriate
ionic conditions, especially appropriate concentrations of
magnesium and calcium. Fourth, during forward motion
of the cilium, the double tubules on the front edge of the
cilium slide outward toward the tip of the cilium, whereas
those on the back edge remain in place. Fifth, multiple
protein arms composed of the protein dynein, which has
adenosine triphosphatase (ATPase) enzymatic activity,
project from each double tubule toward an adjacent dou-
ble tubule.
Given this basic information, it has been determined
that the release of energy from ATP in contact with the
ATPase dynein arms causes the heads of these arms to
“crawl” rapidly along the surface of the adjacent double
tubule. If the front tubules crawl outward while the back
tubules remain stationary, bending occurs.
The way in which cilia contraction is controlled is not
well understood. The cilia of some genetically abnormal
cells do not have the two central single tubules, and these
cilia fail to beat. Therefore, it is presumed that some signal,
perhaps an electrochemical signal, is transmitted along
these two central tubules to activate the dynein arms.
Nonmotile Primary Cilia Serve as Cell Sensory “An-
tennae.” Primary cilia are nonmotile and generally
occur only as a single cilium on each cell. Although the
physiological functions of primary cilia are not fully un-
derstood, current evidence indicates that they function
as cellular ‘’sensory antennae,” which coordinate cellular
signaling pathways involved in chemical and mechani-
cal sensation, signal transduction, and cell growth. In the
kidneys, for example, primary cilia are found in most epi-
thelial cells of the tubules, projecting into the tubule lu-
men and acting as a flow sensor. In response to fluid flow
over the tubular epithelial cells, the primary cilia bend and
cause flow-­induced changes in intracellular calcium sign-
aling. These signals, in turn, initiate multiple effects on
the cells. Defects in signaling by primary cilia in renal tu-
bular epithelial cells are thought to contribute to various
disorders, including the development of large fluid-­filled
cysts, a condition called polycystic kidney disease.
Bibliography
Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 6th
ed. New York: Garland Science, 2014.
Brandizzi F, Barlowe C: Organization of the ER-Golgi interface for
membrane traffic control. Nat Rev Mol Cell Biol 14:382, 2013.
Dikic I, Elazar Z. Mechanism and medical implications of mammalian
autophagy. Nat Rev Mol Cell Biol 19:349, 2018.
Eisner V, Picard M, Hajnóczky G. Mitochondrial dynamics in adap-
tive and maladaptive cellular stress responses. Nat Cell Biol 20:755,
2018.
Galluzzi L, Yamazaki T, Kroemer G. Linking cellular stress responses
to systemic homeostasis. Nat Rev Mol Cell Biol 19:731, 2018.

Guerriero CJ, Brodsky JL: The delicate balance between secreted pro-
tein folding and endoplasmic reticulum-associated degradation in
human physiology. Physiol Rev 92:537, 2012.
Harayama T, Riezman H. Understanding the diversity of membrane
lipid composition. Nat Rev Mol Cell Biol 19:281, 2018.
Insall R: The interaction between pseudopods and extracellular signal-
ling during chemotaxis and directed migration. Curr Opin Cell Biol
25:526, 2013.
Kaksonen M, Roux A. Mechanisms of clathrin-mediated endocytosis.
Nat Rev Mol Cell Biol 19:313, 2018.
Lawrence RE, Zoncu R. The lysosome as a cellular centre for signalling,
metabolism and quality control. Nat Cell Biol 21: 133, 2019.
Nakamura N, Wei JH, Seemann J: Modular organization of the mam-
malian Golgi apparatus. Curr Opin Cell Biol 24:467, 2012.
Chapter 2 The Cell and Its Functions
Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy
in cellular homeostasis, physiology and pathology. Nat Cell Biol
20:1013, 2018.
Sezgin E, Levental I, Mayor S, Eggeling C. The mystery of membrane
organization: composition, regulation and roles of lipid rafts. Nat
Rev Mol Cell Biol 18:361, 2017.
Spinelli JB, Haigis MC. The multifaceted contributions of mitochon-
UNIT I
dria to cellular metabolism. Nat Cell Biol. 20:745, 2018.
Walker CL, Pomatto LCD, Tripathi DN, Davies KJA. Redox regulation
of homeostasis and proteostasis in peroxisomes. Physiol Rev 98:89,
2018.
Zhou K, Gaullier G, Luger K. Nucleosome structure and dynamics are
coming of age. Nat Struct Mol Biol 26:3, 2019.
29
 CHAPTER 3

Genetic Control of Protein Synthesis, Cell

UNIT I
Function, and Cell Reproduction

Genes, which are located in the nuclei of all cells of the Building Blocks of DNA
body, control heredity from parents to children, as well Figure 3-3 shows the basic chemical compounds involved
as the daily functioning of all the body’s cells. The genes in the formation of DNA. These compounds include the
control cell function by determining which structures, following: (1) phosphoric acid; (2) a sugar called deoxyri-
enzymes, and chemicals are synthesized within the cell. bose; and (3) four nitrogenous bases (two purines, adenine
Figure 3-1 shows the general schema of genetic con- and guanine, and two pyrimidines, thymine and cytosine).
trol. Each gene, which is composed of deoxyribonucleic The phosphoric acid and deoxyribose form the two heli-
acid (DNA), controls the formation of another nucleic cal strands that are the backbone of the DNA molecule,
acid, ribonucleic acid (RNA); this RNA then spreads and the nitrogenous bases lie between the two strands
throughout the cell to control formation of a specific pro- and connect them, as illustrated in Figure 3-2.
tein. The entire process, from transcription of the genetic
code in the nucleus to translation of the RNA code and Nucleotides
the formation of proteins in the cell cytoplasm, is often The first stage of DNA formation is to combine one mol-
referred to as gene expression. ecule of phosphoric acid, one molecule of deoxyribose, and
Because the human body has approximately 20,000 one of the four bases to form an acidic nucleotide. Four
to 25,000 different genes that code for proteins in each separate nucleotides are thus formed, one for each of the
cell, it is possible to form a large number of different cel- four bases: deoxyadenylic, deoxythymidylic, deoxyguanylic,
lular proteins. In fact, RNA molecules transcribed from and deoxycytidylic acids. Figure 3-4 shows the chemical
the same segment of DNA—the same gene—can be pro-
cessed in more than one way by the cell, giving rise to
alternate versions of the protein. The total number of
Plasma Nuclear
different proteins produced by the various cell types in membrane envelope
humans is estimated to be at least 100,000.
Some of the cellular proteins are structural proteins,
which, in association with various lipids and carbohy- Nucleus
drates, form structures of the various intracellular organ- DNA Gene (DNA)
elles discussed in Chapter 2. However, most of the proteins DNA Transcription
transcription
are enzymes that catalyze different chemical reactions in
the cells. For example, enzymes promote all the oxidative RNA RNA formation
reactions that supply energy to the cell, along with synthe-
sis of all the cell chemicals, such as lipids, glycogen, and RNA
splicing
adenosine triphosphate (ATP). mRNA Translation

Ribosomes RNA transport

CELL NUCLEUS GENES CONTROL
PROTEIN SYNTHESIS mRNA Protein formation

In the cell nucleus, large numbers of genes are attached end Translation of
mRNA Cell Cell
on end in extremely long, double-­stranded helical molecules
structure enzymes
of DNA having molecular weights measured in the billions.
A very short segment of such a molecule is shown in Figure Protein
Cytosol
3-2. This molecule is composed of several simple chemical Cell function
compounds bound together in a regular pattern, the details Figure 3-1 The general schema whereby genes control cell function.
of which are explained in the next few paragraphs. mRNA, Messenger RNA.

31
UNIT I Introduction to Physiology: The Cell and General Physiology

Adenine NH2 O Thymine Guanine O H2N Cytosine

P A N H T P G H N C
Sugar P Sugar P
Sugar NH2 O Sugar

Sugar-phosphate Sugar-phosphate
backbone backbone
5’
5’

C T
G T G C A T
C

3’ G C A C G T
A G A

Base pairs Base pairs

3’
Figure 3-2 The helical double-­stranded structure of the gene. The outside strands are composed of phosphoric acid and the sugar deoxyribose.
The internal molecules connecting the two strands of the helix are purine and pyrimidine bases, which determine the “code” of the gene.

Phosphoric acid O

H O P O H

H
Deoxyribose H
H H
O C O H
H O C C
C H
C
H
H
H
O

H
Bases H H
N H O
N C N C H
C N
H C O C C C H
C C H
N N N C H
H H H
Adenine Thymine
H
O
N H
N C N C
C N H
H C H O C C H
C C N
N N H N C
H H H
Guanine Cytosine
Purines Pyrimidines

Figure 3-3 The basic building blocks of DNA.

32
 Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

structure of deoxyadenylic acid, and Figure 3-5 shows lines) between the purine and pyrimidine bases, the two
simple symbols for the four nucleotides that form DNA. respective DNA strands are held together. Note the fol-
lowing caveats, however:
Nucleotides Are Organized to Form Two 1. Each purine base adenine of one strand always bonds
Strands of DNA Loosely Bound to Each with a pyrimidine base thymine of the other strand.
Other 2. Each purine base guanine always bonds with a py-

UNIT I
Figure 3-2 shows the manner in which multiple nucleo- rimidine base cytosine.
tides are bound together to form two strands of DNA. The Thus, in Figure 3-6, the sequence of complementary
two strands are, in turn, loosely bonded with each other pairs of bases is CG, CG, GC, TA, CG, TA, GC, AT, and
by weak cross-­linkages, as illustrated in Figure 3-6 by the AT. Because of the looseness of the hydrogen bonds, the
central dashed lines. Note that the backbone of each DNA two strands can pull apart with ease, and they do so many
strand is composed of alternating phosphoric acid and times during the course of their function in the cell.
deoxyribose molecules. In turn, purine and pyrimidine To put the DNA of Figure 3-6 into its proper physical
bases are attached to the sides of the deoxyribose mol- perspective, one could merely pick up the two ends and
ecules. Then, by means of loose hydrogen bonds (dashed twist them into a helix. Ten pairs of nucleotides are pres-
ent in each full turn of the helix in the DNA molecule.
H H
N
Adenine
N C GENETIC CODE
C N
H C The importance of DNA lies in its ability to control the
Phosphate C C H formation of proteins in the cell, which it achieves by
N N
O H H
O
means of a genetic code. That is, when the two strands of
C H Deoxyribose
a DNA molecule are split apart, the purine and pyrimi-
H O P O C C
C H dine bases projecting to the side of each DNA strand are
C
O H exposed, as shown by the top strand in Figure 3-7. It is
H O H
H
these projecting bases that form the genetic code.
H The genetic code consists of successive “triplets” of
bases—that is, each three successive bases is a code word.
Figure 3-4. Deoxyadenylic acid, one of the nucleotides that make
up DNA. The successive triplets eventually control the sequence of
amino acids in a protein molecule that is to be synthe-
sized in the cell. Note in Figure 3-6 that the top strand
of DNA, reading from left to right, has the genetic code
GGC, AGA, CTT, with the triplets being separated from
A T one another by the arrows. As we follow this genetic code
through Figure 3-7 and Figure 3-8, we see that these
P D P D
Deoxyadenylic acid Deoxythymidylic acid three respective triplets are responsible for successive
placement of the three amino acids, proline, serine, and
glutamic acid, in a newly formed molecule of protein.

TRANSCRIPTION—TRANSFER OF CELL
G C
NUCLEUS DNA CODE TO CYTOPLASM
P D P D RNA CODE
Deoxyguanylic acid Deoxycytidylic acid
Because DNA is located in the cell nucleus, yet most of
Figure 3-5. Symbols for the four nucleotides that combine to form
DNA. Each nucleotide contains phosphoric acid (P), deoxyribose (D),
the cell functions are carried out in the cytoplasm, there
and one of the four nucleotide bases: adenine (A); thymine (T); gua- must be some means for DNA genes of the nucleus to
nine (G); or cytosine (C). control chemical reactions of the cytoplasm. This control

P D P D P D P D P D P D P D P D P D P

G G C A G A C T T

C C G T C T G A A

P D P D P D P D P D P D P D P D P D
Figure 3-6. Arrangement of deoxyribose nucleotides
in a double strand of DNA.

33
UNIT I Introduction to Physiology: The Cell and General Physiology

DNA strand
D P D P D P D P D P D P D P D P D P

G G C A G A C T T

C C G U C U G A

Figure 3-7. Combination of ribose nucleotides R

P R P R P R P R P R P R P R P
with a strand of DNA to form a molecule of RNA Triphosphate
RNA molecule
that carries the genetic code from the gene to the P P
cytoplasm. The RNA polymerase enzyme moves P P
along the DNA strand and builds the RNA mol-
ecule. RNA polymerase

C C G U C U G A A
Figure 3-8. A portion of an RNA molecule showing three
RNA codons—CCG, UCU, and GAA—that control attachment P R P R P R P R P R P R P R P R P R
of the three amino acids, proline, serine, and glutamic acid,
respectively, to the growing RNA chain. Proline Serine Glutamic acid

is achieved through the intermediary of another type of
nucleic acid, RNA, the formation of which is controlled
by DNA of the nucleus. Thus, as shown in Figure 3-7, the
code is transferred to RNA in a process called transcrip-
tion. The RNA, in turn, diffuses from the nucleus through
nuclear pores into the cytoplasmic compartment, where
it controls protein synthesis.
RNA IS SYNTHESIZED IN THE NUCLEUS
FROM A DNA TEMPLATE
During RNA synthesis, the two strands of DNA separate
temporarily; one of these strands is used as a template for
synthesis of an RNA molecule. The code triplets in the
DNA result in the formation of complementary code trip-
lets (called codons) in the RNA. These codons, in turn,
will control the sequence of amino acids in a protein to be
synthesized in the cell cytoplasm.
Building Blocks of RNA. The basic building blocks of
RNA are almost the same as those of DNA, except for
two differences. First, the sugar deoxyribose is not used
in RNA formation. In its place is another sugar of slightly
different composition, ribose, which contains an extra hy-
droxyl ion appended to the ribose ring structure. Second,
thymine is replaced by another pyrimidine, uracil.
Formation of RNA Nucleotides. The basic building
blocks of RNA form RNA nucleotides, exactly as described
previously for DNA synthesis. Here again, four separate
nucleotides are used to form RNA. These nucleotides
contain the bases adenine, guanine, cytosine, and uracil.
Note that these bases are the same as in DNA, except that
uracil in RNA replaces thymine in DNA.
“Activation” of RNA Nucleotides. The next step in the
synthesis of RNA is “activation” of RNA nucleotides by an
enzyme, RNA polymerase. This activation occurs by add-
ing two extra phosphate radicals to each nucleotide to form
triphosphates (shown in Figure 3-7 by the two RNA nucleo-
tides to the far right during RNA chain formation). These
last two phosphates are combined with the nucleotide by
high-­energy phosphate bonds derived from ATP in the cell.
The result of this activation process is that large quan-
tities of ATP energy are made available to each of the
nucleotides. This energy is used to promote chemical
reactions that add each new RNA nucleotide at the end of
the developing RNA chain.
RNA CHAIN ASSEMBLY FROM ACTIVATED
NUCLEOTIDES USING THE DNA STRAND
AS A TEMPLATE
As shown in Figure 3-7, assembly of RNA is accomplished
under the influence of an enzyme, RNA polymerase. This
large protein enzyme has many functional properties nec-
essary for formation of RNA, as follows:
1. In the DNA strand immediately ahead of the gene
to be transcribed is a sequence of nucleotides called
the promoter. The RNA polymerase has an appro-
priate complementary structure that recognizes this
promoter and becomes attached to it, which is the
essential step for initiating the formation of RNA.
2. After the RNA polymerase attaches to the promot-
er, the polymerase causes unwinding of about two
turns of the DNA helix and separation of the un-
wound portions of the two strands.
3. The polymerase then moves along the DNA strand,
temporarily unwinding and separating the two
DNA strands at each stage of its movement. As it
moves along, at each stage it adds a new activated
RNA nucleotide to the end of the newly forming
RNA chain through the following steps:
a. First, it causes a hydrogen bond to form between
the end base of the DNA strand and the base of
an RNA nucleotide in the nucleoplasm.

34
 Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

b. Then, one at a time, the RNA polymerase breaks structures on which protein molecules are actually
two of the three phosphate radicals away from each assembled.
of these RNA nucleotides, liberating large amounts 6. MicroRNAs (miRNAs) are single-­ stranded RNA
of energy from the broken high-­energy phosphate molecules of 21 to 23 nucleotides that can regulate
bonds. This energy is used to cause covalent linkage gene transcription and translation.
of the remaining phosphate on the nucleotide with
MESSENGER RNA—THE CODONS

UNIT I
the ribose on the end of the growing RNA chain.
c. When the RNA polymerase reaches the end of Messenger RNA molecules are long single RNA strands
the DNA gene, it encounters a new sequence of that are suspended in the cytoplasm. These molecules are
DNA nucleotides called the chain-­terminating composed of several hundred to several thousand RNA
sequence, which causes the polymerase and the nucleotides in unpaired strands, and they contain codons
newly formed RNA chain to break away from the that are exactly complementary to the code triplets of the
DNA strand. The polymerase then can be used DNA genes. Figure 3-8 shows a small segment of mRNA.
again and again to form more new RNA chains. Its codons are CCG, UCU, and GAA, which are the
d. As the new RNA strand is formed, its weak hy- codons for the amino acids proline, serine, and glutamic
drogen bonds with the DNA template break acid. The transcription of these codons from the DNA
away because the DNA has a high affinity for molecule to the RNA molecule is shown in Figure 3-7.
rebonding with its own complementary DNA
strand. Thus, the RNA chain is forced away from RNA Codons for the Different Amino Acids. Table 3-1
the DNA and is released into the nucleoplasm. lists the RNA codons for the 20 common amino acids
Therefore, the code that is present in the DNA strand found in protein molecules. Note that most of the amino
is eventually transmitted in complementary form to the acids are represented by more than one codon; also, one
RNA chain. The ribose nucleotide bases always combine codon represents the signal “start manufacturing the pro-
with the deoxyribose bases in the following combinations: tein molecule,” and three codons represent “stop manu-
facturing the protein molecule.” In Table 3-1, these two
DNA Base RNA Base
guanine Cytosine
cytosine Guanine Table 3-1 RNA Codons for Amino Acids and for Start
and Stop
adenine Uracil
thymine adenine Amino Acid RNA Codons
Alanine GCU GCC GCA GCG
There Are Several Different Types of RNA. As research
Arginine CGU CGC CGA CGG AGA AGG
on RNA has continued to advance, many different types
of RNA have been discovered. Some types of RNA are in- Asparagine AAU AAC
volved in protein synthesis, whereas other types serve gene Aspartic acid GAU GAC
regulatory functions or are involved in posttranscription- Cysteine UGU UGC
al modification of RNA. The functions of some types of Glutamic acid GAA GAG
RNA, especially those that do not appear to code for pro-
Glutamine CAA CAG
teins, are still mysterious. The following six types of RNA
Glycine GGU GGC GGA GGG
play independent and different roles in protein synthesis:
1. Precursor messenger RNA (pre-­mRNA) is a large, Histidine CAU CAC
immature, single strand of RNA that is processed Isoleucine AUU AUC AUA
in the nucleus to form mature messenger RNA Leucine CUU CUC CUA CUG UUA UUG
(mRNA). The pre-­RNA includes two different types Lysine AAA AAG
of segments, called introns, which are removed by
Methionine AUG
a process called splicing, and exons, which are re-
Phenylalanine UUU UUC
tained in the final mRNA.
2. Small nuclear RNA (snRNA) directs the splicing of Proline CCU CCC CCA CCG
pre-­mRNA to form mRNA. Serine UCU UCC UCA UCG AGC AGU
3. Messenger RNA (mRNA) carries the genetic code Threonine ACU ACC ACA ACG
to the cytoplasm for controlling the type of protein Tryptophan UGG
formed. Tyrosine UAU UAC
4. Transfer RNA (tRNA) transports activated amino
Valine GUU GUC GUA GUG
acids to the ribosomes to be used in assembling the
protein molecule. Start (CI) AUG
5. Ribosomal RNA, along with about 75 different pro- Stop (CT) UAA UAG UGA
teins, forms ribosomes, the physical and chemical CI, Chain-­initiating; CT, chain-­terminating.

35
UNIT I Introduction to Physiology: The Cell and General Physiology
types of codons are designated CI for “chain-­initiating”
or “start” codon and CT for “chain-­terminating” or “stop”
codon.
TRANSFER RNA—THE ANTICODONS
Another type of RNA that is essential for protein synthesis
is called transfer RNA (tRNA) because it transfers amino
acids to protein molecules as the protein is being syn-
thesized. Each type of tRNA combines specifically with
1 of the 20 amino acids that are to be incorporated into
proteins. The tRNA then acts as a carrier to transport its
specific type of amino acid to the ribosomes, where pro-
tein molecules are forming. In the ribosomes, each spe-
cific type of tRNA recognizes a particular codon on the
mRNA (described later) and thereby delivers the appro-
priate amino acid to the appropriate place in the chain of
the newly forming protein molecule.
Transfer RNA, which contains only about 80 nucleo-
tides, is a relatively small molecule in comparison with
mRNA. It is a folded chain of nucleotides with a cloverleaf
appearance similar to that shown in Figure 3-9. At one
end of the molecule there is always an adenylic acid to
which the transported amino acid attaches at a hydroxyl
group of the ribose in the adenylic acid.
Because the function of tRNA is to cause attachment
of a specific amino acid to a forming protein chain, it is
essential that each type of tRNA also have specificity for
a particular codon in the mRNA. The specific code in the
tRNA that allows it to recognize a specific codon is again
a triplet of nucleotide bases and is called an anticodon.
This anticodon is located approximately in the middle of
the tRNA molecule (at the bottom of the cloverleaf con-
figuration shown in Figure 3-9). During formation of the
protein molecule, the anticodon bases combine loosely by
hydrogen bonding with the codon bases of the mRNA. In
this way, the respective amino acids are lined up one after
another along the mRNA chain, thus establishing the
Alanine
Cysteine
Forming protein
Histidine
Alanine
Phenylalanine
Serine
Transfer RNA Proline
Start codon
Anticodon
Codon
GGG
AUG GCC UGU CAU GCC UUU UCC CCC AAA CAG GAC UAU
Ribosome Ribosome
Messenger
RNA movement
Figure 3-9. A messenger RNA strand is moving through two ribo-
somes. As each codon passes through, an amino acid is added to the
growing protein chain, which is shown in the right-­hand ribosome.
The transfer RNA molecule transports each specific amino acid to the
newly forming protein.
36
appropriate sequence of amino acids in the newly form-
ing protein molecule.
RIBOSOMAL RNA
The third type of RNA in the cell is ribosomal RNA,
which constitutes about 60% of the ribosome. The remain-
der of the ribosome is protein, including about 75 types
of proteins that are both structural proteins and enzymes
needed to manufacture proteins.
The ribosome is the physical structure in the cytoplasm
on which proteins are actually synthesized. However, it
always functions in association with the other two types
of RNA; tRNA transports amino acids to the ribosome
for incorporation into the developing protein, whereas
mRNA provides the information necessary for sequenc-
ing the amino acids in proper order for each specific type
of protein to be manufactured. Thus, the ribosome acts
as a manufacturing plant in which the protein molecules
are formed.
Formation of Ribosomes in the Nucleolus. The DNA
genes for the formation of ribosomal RNA are located in
five pairs of chromosomes in the nucleus. Each of these
chromosomes contains many duplicates of these particu-
lar genes because of the large amounts of ribosomal RNA
required for cellular function.
As the ribosomal RNA forms, it collects in the nucleo-
lus, a specialized structure lying adjacent to the chromo-
somes. When large amounts of ribosomal RNA are being
synthesized, as occurs in cells that manufacture large
amounts of protein, the nucleolus is a large structure,
whereas in cells that synthesize little protein, the nucle-
olus may not even be seen. Ribosomal RNA is specially
processed in the nucleolus, where it binds with ribosomal
proteins to form granular condensation products that
are primordial subunits of ribosomes. These subunits are
then released from the nucleolus and transported through
the large pores of the nuclear envelope to almost all parts
of the cytoplasm. After the subunits enter the cytoplasm,
they are assembled to form mature functional ribosomes.
Therefore, proteins are formed in the cytoplasm of the
cell, but not in the cell nucleus, because the nucleus does
not contain mature ribosomes.
miRNA AND SMALL INTERFERING RNA
A fourth type of RNA in the cell is microRNA (miRNA);
miRNA are short (21 to 23 nucleotides) single-­stranded
RNA fragments that regulate gene expression (Figure
3-10). The miRNAs are encoded from the transcribed
DNA of genes, but they are not translated into pro-
teins and are therefore often called noncoding RNA. The
miRNAs are processed by the cell into molecules that
are complementary to mRNA and act to decrease gene
expression. The generation of miRNAs involves special
processing of longer primary precursor RNAs called pri-­
miRNAs, which are the primary transcripts of the gene.
 Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

Another type of miRNA is small interfering RNA

Protein-coding gene miRNA (siRNA), also called silencing RNA or short interfering
RNA. The siRNAs are short, double-­stranded RNA mol-
ecules, comprised of 20 to 25 nucleotides, that interfere
Transcription Transcription
with expression of specific genes. siRNAs generally refer
of mRNA of pri-miRNA to synthetic miRNAs and can be administered to silence

UNIT I
pri-miRNA expression of specific genes. They are designed to avoid
nuclear processing by the microprocessor complex and,
Microprocessor after the siRNA enters the cytoplasm, it activates the RISC
complex silencing complex, blocking the translation of mRNA.
Because siRNAs can be tailored for any specific sequence
Nucleus in the gene, they can be used to block translation of any
pre-miRNA mRNA and therefore expression by any gene for which
the nucleotide sequence is known. Researchers have pro-
Cytoplasm posed that siRNAs may become useful therapeutic tools
Transport of pre-miRNA
into cytoplasm to silence genes that contribute to the pathophysiology of
diseases.

Dicer
Processing of
pre-miRNA into small
RNA duplexes
RISC
mRNA
RISC-miRNA
complex
mRNA degradation Translational repression
Figure 3-10. Regulation of gene expression by microRNA (miRNA).
Primary miRNA (pri-­miRNA), the primary transcripts of a gene pro-
cessed in the cell nucleus by the microprocessor complex, are con-
verted to pre-­miRNAs. These pre-­miRNAs are then further processed
in the cytoplasm by dicer, an enzyme that helps assemble an RNA-­
induced silencing complex (RISC) and generates miRNAs. The miRNAs
regulate gene expression by binding to the complementary region of
the RNA and repressing translation or promoting degradation of the
messenger RNA (mRNA) before it can be translated by the ribosome.
The pri-­miRNAs are then processed in the cell nucleus
by the microprocessor complex to pre-­miRNAs, which are
70-­nucleotide, stem loop structures. These pre-­miRNAs
are then further processed in the cytoplasm by a specific
dicer enzyme that helps assemble an RNA-­induced silenc-
ing complex (RISC) and generates miRNAs.
The miRNAs regulate gene expression by binding to the
complementary region of the RNA and promoting repres-
sion of translation or degradation of the mRNA before it
can be translated by the ribosome. miRNAs are believed to
play an important role in normal regulation of cell function,
and alterations in miRNA function have been associated
with diseases such as cancer and heart disease.
TRANSLATION—FORMATION OF
PROTEINS ON THE RIBOSOMES
When a molecule of mRNA comes in contact with a
ribosome, it travels through the ribosome, beginning at
a predetermined end of the RNA molecule specified by
an appropriate sequence of RNA bases called the chain-­
initiating codon. Then, as shown in Figure 3-9, while the
mRNA travels through the ribosome, a protein molecule
is formed, a process called translation. Thus, the ribo-
some reads the codons of the mRNA in much the same
way that a tape is read as it passes through the playback
head of a tape recorder. Then, when a “stop” (or “chain-­
terminating”) codon slips past the ribosome, the end of a
protein molecule is signaled, and the protein molecule is
freed into the cytoplasm.
Polyribosomes. A single mRNA molecule can form
protein molecules in several ribosomes at the same time
because the initial end of the RNA strand can pass to a
successive ribosome as it leaves the first, as shown at the
bottom left in Figure 3-9 and Figure 3-11. The protein
molecules are in different stages of development in each
ribosome. As a result, clusters of ribosomes frequently
occur, with 3 to 10 ribosomes being attached to a single
mRNA at the same time. These clusters are called polyri-
bosomes.
An mRNA can cause formation of a protein molecule
in any ribosome; there is no specificity of ribosomes for
given types of protein. The ribosome is simply the physi-
cal manufacturing plant in which the chemical reactions
take place.
Many Ribosomes Attach to the Endoplasmic
Reticulum. In Chapter 2, we noted that many ribosomes
become attached to the endoplasmic reticulum. This at-
tachment occurs because the initial ends of many forming
protein molecules have amino acid sequences that imme-
diately attach to specific receptor sites on the endoplas-
mic reticulum, causing these molecules to penetrate the

37
UNIT I Introduction to Physiology: The Cell and General Physiology
Messenger
RNA
Transfer RNA
Figure 3-11. The physical structure
of the ribosomes, as well as their
functional relationship to messenger
RNA, transfer RNA, and the endo-
Amino acid Endoplasmic
plasmic reticulum during the forma- reticulum
tion of protein molecules.
reticulum wall and enter the endoplasmic reticulum ma-
trix. This process gives a granular appearance to the por-
tions of the reticulum where proteins are being formed
and are entering the matrix of the reticulum.
Figure 3-11 shows the functional relationship of
mRNA to the ribosomes and the manner in which the
ribosomes attach to the membrane of the endoplasmic
reticulum. Note the process of translation occurring in
several ribosomes at the same time in response to the
same strand of mRNA. Note also the newly forming poly-
peptide (protein) chains passing through the endoplasmic
reticulum membrane into the endoplasmic matrix.
It should be noted that except in glandular cells, in
which large amounts of protein-­containing secretory ves-
icles are formed, most proteins synthesized by the ribo-
somes are released directly into the cytosol instead of into
the endoplasmic reticulum. These proteins are enzymes
and internal structural proteins of the cell.
Chemical Steps in Protein Synthesis. Some of the
chemical events that occur in the synthesis of a protein
molecule are shown in Figure 3-12. This Fig. shows rep-
resentative reactions for three separate amino acids, AA1,
AA2, and AA20. The stages of the reactions are as follows:
1. Each amino acid is activated by a chemical pro-
cess in which ATP combines with the amino acid
to form an adenosine monophosphate complex with
the amino acid, giving up two high-­energy phos-
phate bonds in the process.
2. The activated amino acid, having an excess of ener-
gy, then combines with its specific tRNA to form an
amino acid–tRNA complex and, at the same time,
releases the adenosine monophosphate.
3. The tRNA carrying the amino acid complex then
comes in contact with the mRNA molecule in the
ribosome, where the anticodon of the tRNA attach-
es temporarily to its specific codon of the mRNA,
thus lining up the amino acid in the appropriate se-
quence to form a protein molecule.
Then, under the influence of the enzyme peptidyl
transferase (one of the proteins in the ribosome), peptide
bonds are formed between the successive amino acids,
thus adding progressively to the protein chain. These
38
Ribosome
Small
subunit
Large
subunit
Polypeptide
chain
chemical events require energy from two additional
high-­energy phosphate bonds, making a total of four
high-­energy bonds used for each amino acid added to the
protein chain. Thus, the synthesis of proteins is one of the
most energy-­consuming processes of the cell.
Peptide Linkage—Combination of Amino Acids. The
successive amino acids in the protein chain combine
with one another according to the typical reaction.
NH2 O H R
R C C OH + H N C COOH
NH2 O H R
R C C N C COOH + H2O
In this chemical reaction, a hydroxyl radical (OH−) is
removed from the COOH portion of the first amino acid,
and a hydrogen (H+) of the NH2 portion of the other amino
acid is removed. These combine to form water, and the
two reactive sites left on the two successive amino acids
bond with each other, resulting in a single molecule. This
process is called peptide linkage. As each additional amino
acid is added, an additional peptide linkage is formed.
SYNTHESIS OF OTHER SUBSTANCES IN
THE CELL
Many thousand protein enzymes formed in the manner
just described control essentially all the other chemical
reactions that take place in cells. These enzymes promote
synthesis of lipids, glycogen, purines, pyrimidines, and
hundreds of other substances. We discuss many of these
synthetic processes in relation to carbohydrate, lipid, and
protein metabolism in Chapters 68 through 70. These sub-
stances each contribute to the various functions of the cells.
CONTROL OF GENE FUNCTION AND
BIOCHEMICAL ACTIVITY IN CELLS
From our discussion thus far, it is clear that the genes control
both the physical and chemical functions of the cells. How-
ever, the degree of activation of respective genes must also be
 Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

Amino acid AA1 AA2 AA20

+ + +
ATP ATP ATP

Activated amino acid AMP AA1 AMP AA2 AMP AA20

+ + +
tRNA1 tRNA2 tRNA20

UNIT I
RNA–amino acyl complex tRNA1 AA1 tRNA2 AA2 tRNA20 AA20
+ + +

Messenger RNA GCC UGU AAU CAU CGU AUG GUU

GCC UGU AAU CAU CGU AUG GUU

Complex between tRNA,

tRNA13

tRNA20
tRNA1

tRNA5

tRNA3

tRNA9

tRNA2
messenger RNA, and
amino acid
AA1

AA5

AA3

AA9

AA2

AA13

AA20
Figure 3-12. Chemical events in the formation of a pro-
GTP GTP GTP GTP GTP GTP GTP tein molecule. AMP, Adenosine monophosphate; ATP,
adenosine triphosphate; GTP, guanosine triphosphate;
Protein chain AA1 AA5 AA3 AA9 AA2 AA13 AA20
tRNA, transfer RNA.

controlled; otherwise, some parts of the cell might overgrow Condensed Upstream
or some chemical reactions might overact until they kill the chromatin
Insulator
cell. Each cell has powerful internal feedback control mecha- Enhan
cer
nisms that keep the various functional operations of the cell
in step with one another. For each gene (≈20,000–25,000 Transcription
inhibitors
genes in all), at least one such feedback mechanism exists. Transcription
There are basically two methods whereby the biochem- factors RNA polymerase 2
ical activities in the cell are controlled: (1) genetic regula-
tion, in which the degree of activation of the genes and
RE RE TATA INR
the formation of gene products are themselves controlled,
and (2) enzyme regulation, in which the activity levels of Proximal promoter
already formed enzymes in the cell are controlled. elements Basal promoter
Figure 3-13. Gene transcription in eukaryotic cells. A complex ar-
rangement of multiple clustered enhancer modules is interspersed with
GENETIC REGULATION
insulator elements, which can be located upstream or downstream of
Genetic regulation, or regulation of gene expression, covers a basal promoter containing TATA box (TATA), proximal promoter ele-
ments (response elements, RE), and initiator sequences (INR).
the entire process from transcription of the genetic code in
the nucleus to the formation of proteins in the cytoplasm. controlled by regulatory elements found in the promoter
Regulation of gene expression provides all living organismsof a gene (Figure 3-13). In eukaryotes, which includes all
with the ability to respond to changes in their environment.
mammals, the basal promoter consists of a sequence of
In animals that have many different types of cells, tissues,
bases (TATAAA) called the TATA box, the binding site
and organs, differential regulation of gene expression alsofor the TATA-­binding protein and several other impor-
permits the different cell types in the body to each perform
tant transcription factors that are collectively referred to
their specialized functions. Although a cardiac myocyte as the transcription factor IID complex. In addition to the
contains the same genetic code as a renal tubular epithelial
transcription factor IID complex, this region is where
cell, many genes are expressed in cardiac cells that are not
transcription factor IIB binds to both the DNA and RNA
expressed in renal tubular cells. The ultimate measure of polymerase 2 to facilitate transcription of the DNA into
gene “expression” is whether (and how much) of the gene RNA. This basal promoter is found in all protein-­coding
products (proteins) are produced because proteins carry genes, and the polymerase must bind with this basal
out cell functions specified by the genes. Regulation of gene
promoter before it can begin traveling along the DNA
expression can occur at any point in the pathways of tran- strand to synthesize RNA. The upstream promoter is lo-
scription, RNA processing, and translation. cated farther upstream from the transcription start site
and contains several binding sites for positive or negative
The Promoter Controls Gene Expression. Synthesis transcription factors that can affect transcription through
of cellular proteins is a complex process that starts with interactions with proteins bound to the basal promoter.
transcription of DNA into RNA. Transcription of DNA is The structure and transcription factor binding sites in the
39
UNIT I Introduction to Physiology: The Cell and General Physiology
upstream promoter vary from gene to gene to give rise
to the different expression patterns of genes in different
tissues.
Transcription of genes in eukaryotes is also influenced
by enhancers, which are regions of DNA that can bind
transcription factors. Enhancers can be located a great
distance from the gene they act on or even on a differ-
ent chromosome. They can also be located upstream or
downstream of the gene that they regulate. Although
enhancers may be located far from their target gene, they
may be relatively close when DNA is coiled in the nucleus.
It is estimated that there are more than 100,000 gene
enhancer sequences in the human genome.
In the organization of the chromosome, it is important
to separate active genes that are being transcribed from
genes that are repressed. This separation can be challeng-
ing because multiple genes may be located close together
on the chromosome. The separation is achieved by chro-
mosomal insulators. These insulators are gene sequences
that provide a barrier so that a specific gene is isolated
against transcriptional influences from surrounding genes.
Insulators can vary greatly in their DNA sequence and the
proteins that bind to them. One way an insulator activity
can be modulated is by DNA methylation, which is the
case for the mammalian insulin-­like growth factor 2 (IGF-­
2) gene. The mother’s allele has an insulator between the
enhancer and promoter of the gene that allows for the
binding of a transcriptional repressor. However, the pater-
nal DNA sequence is methylated such that the transcrip-
tional repressor cannot bind to the insulator, and the IGF-­2
gene is expressed from the paternal copy of the gene.
Other Mechanisms for Control of Transcription by the
Promoter. Variations in the basic mechanism for control
of the promoter have been discovered in the past three
decades. Without giving details, let us list some of them:
1. A promoter is frequently controlled by transcrip-
tion factors located elsewhere in the genome. That
is, the regulatory gene causes the formation of a
regulatory protein that in turn acts as an activator
or repressor of transcription.
2. Occasionally, many different promoters are con-
trolled at the same time by the same regulatory
protein. In some cases, the same regulatory protein
functions as an activator for one promoter and as a
repressor for another promoter.
3. Some proteins are controlled not at the starting
point of transcription on the DNA strand but far-
ther along the strand. Sometimes, the control is not
even at the DNA strand itself but occurs during the
processing of the RNA molecules in the nucleus be-
fore they are released into the cytoplasm. Control
may also occur at the level of protein formation in
the cytoplasm during RNA translation by the ribo-
somes.
4. In nucleated cells, the nuclear DNA is packaged in
specific structural units, the chromosomes. Within
40
each chromosome, the DNA is wound around small
proteins called histones, which in turn are held
tightly together in a compacted state by still other
proteins. As long as the DNA is in this compacted
state, it cannot function to form RNA. However,
multiple control mechanisms are being discovered
that can cause selected areas of chromosomes to
become decompacted one part at a time, so that
partial RNA transcription can occur. Even then,
specific transcriptor factors control the actual rate
of transcription by the promoter in the chromo-
some. Thus, still higher orders of control are used
to establish proper cell function. In addition, signals
from outside the cell, such as some of the body’s
hormones, can activate specific chromosomal areas
and specific transcription factors, therefore control-
ling the chemical machinery for function of the cell.
Because there are many thousands of different genes
in each human cell, the large number of ways in which
genetic activity can be controlled is not surprising. The
gene control systems are especially important for control-
ling intracellular concentrations of amino acids, amino
acid derivatives, and intermediate substrates and prod-
ucts of carbohydrate, lipid, and protein metabolism.
CONTROL OF INTRACELLULAR FUNCTION
BY ENZYME REGULATION
In addition to control of cell function by genetic regula-
tion, cell activities are also controlled by intracellular
inhibitors or activators that act directly on specific intra-
cellular enzymes. Thus, enzyme regulation represents
a second category of mechanisms whereby cellular bio-
chemical functions can be controlled.
Enzyme Inhibition. Some chemical substances formed
in the cell have direct feedback effects to inhibit the spe-
cific enzyme systems that synthesize them. Almost al-
ways, the synthesized product acts on the first enzyme
in a sequence, rather than on the subsequent enzymes,
usually binding directly with the enzyme and causing an
allosteric conformational change that inactivates it. One
can readily recognize the importance of inactivating the
first enzyme because this prevents buildup of intermedi-
ary products that are not used.
Enzyme inhibition is another example of negative feed-
back control. It is responsible for controlling intracellular
concentrations of multiple amino acids, purines, pyrimi-
dines, vitamins, and other substances.
Enzyme Activation. Enzymes that are normally inac-
tive often can be activated when needed. An example of
this phenomenon occurs when most of the ATP has been
depleted in a cell. In this case, a considerable amount of
cyclic adenosine monophosphate (cAMP) begins to be
formed as a breakdown product of ATP. The presence of
this cAMP, in turn, immediately activates the glycogen-­
splitting enzyme phosphorylase, liberating glucose mole-
 Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
cules that are rapidly metabolized, with their energy used
for replenishment of the ATP stores. Thus, cAMP acts as
an enzyme activator for the enzyme phosphorylase and
thereby helps control intracellular ATP concentration.
Another interesting example of both enzyme inhibi-
tion and enzyme activation occurs in the formation of the
purines and pyrimidines. These substances are needed by
the cell in approximately equal quantities for the formation
of DNA and RNA. When purines are formed, they inhibit
the enzymes that are required for formation of additional
purines. However, they activate the enzymes for formation
of pyrimidines. Conversely, the pyrimidines inhibit their
own enzymes but activate the purine enzymes. In this way,
there is continual cross-­talk between the synthesizing sys-
tems for these two substances, resulting in almost exactly
equal amounts of the two substances in the cells at all times.
Summary. There are two principal mechanisms whereby
cells control proper proportions and quantities of different
cellular constituents: (1) genetic regulation; and (2) enzyme
regulation. The genes can be activated or inhibited, and
likewise, the enzyme systems can be activated or inhibited.
These regulatory mechanisms usually function as feedback
control systems that continually monitor the cell’s biochem-
ical composition and make corrections as needed. However,
on occasion, substances from outside the cell (especially
some of the hormones discussed in this text) also control
the intracellular biochemical reactions by activating or in-
hibiting one or more of the intracellular control systems.
THE DNA–GENETIC SYSTEM CONTROLS
CELL REPRODUCTION
Cell reproduction is another example of the ubiquitous
role that the DNA–genetic system plays in all life pro-
cesses. The genes and their regulatory mechanisms deter-
mine cell growth characteristics and when or whether
cells will divide to form new cells. In this way, the all-­
important genetic system controls each stage in the devel-
opment of the human, from the single-­cell fertilized ovum
to the whole functioning body. Thus, if there is any central
theme to life, it is the DNA–genetic system.
Life Cycle of the Cell
The life cycle of a cell is the period from cell reproduction
to the next cell reproduction. When mammalian cells are
not inhibited and are reproducing as rapidly as they can,
this life cycle may be as little as 10 to 30 hours. It is termi-
nated by a series of distinct physical events called mito-
sis that cause division of the cell into two new daughter
cells. The events of mitosis are shown in Figure 3-14 and
described later. The actual stage of mitosis, however, lasts
for only about 30 minutes, and thus more than 95% of the
life cycle of even rapidly reproducing cells is represented
by the interval between mitosis, called interphase.
Except in special conditions of rapid cellular repro-
duction, inhibitory factors almost always slow or stop the
Centromere Chromosome
Nuclear
membrane
Nucleolus
UNIT I
Centriole
Aster
A B
C D
E F
G H
Figure 3-14. Stages of cell reproduction. A, B, C, Prophase. D, Pro-
metaphase. E, Metaphase. F, Anaphase. G, H, Telophase.
uninhibited life cycle of the cell. Therefore, different cells of
the body actually have life cycle periods that vary from as
little as 10 hours for highly stimulated bone marrow cells to
an entire lifetime of the human body for many nerve cells.
Cell Reproduction Begins with Replication
of DNA
The first step of cell reproduction is replication (duplica-
tion) of all DNA in the chromosomes. It is only after this
replication has occurred that mitosis can take place.
The DNA begins to be duplicated 5 to 10 hours before
mitosis, and the duplication is completed in 4 to 8 hours.
The net result is two exact replicas of all DNA. These rep-
licas become the DNA in the two new daughter cells that
will be formed at mitosis. After replication of the DNA,
there is another period of 1 to 2 hours before mitosis begins
abruptly. Even during this period, preliminary changes that
will lead to the mitotic process are beginning to take place.
DNA Replication. DNA is replicated in much the same
way that RNA is transcribed from DNA, except for a few
important differences:
1. Both strands of the DNA in each chromosome are
replicated, not just one of them.
41
UNIT I Introduction to Physiology: The Cell and General Physiology
Replication fork
Parent Topoisomerase
DNA
strands
5’
Primase RNA
primer
3’
Helicase
Parent DNA strands
Newly synthesized strands
Figure 3-15. DNA replication, showing the replication fork and leading and lagging strands of DNA.
2. Both entire strands of the DNA helix are replicated
from end to end, rather than small portions of them,
as occurs in the transcription of RNA.
3. Multiple enzymes called DNA polymerase, which
is comparable to RNA polymerase, are essential for
replicating DNA. DNA polymerase attaches to and
moves along the DNA template strand, adding nu-
cleotides in the 5′ to 3′ direction. Another enzyme,
DNA ligase, causes bonding of successive DNA nu-
cleotides to one another, using high-­energy phos-
phate bonds to energize these attachments.
4. Replication fork formation. Before DNA can be
replicated, the double-­stranded molecule must be
“unzipped” into two single strands (Figure 3-15).
Because the DNA helixes in each chromosome are
approximately 6 centimeters in length and have mil-
lions of helical turns, it would be impossible for the
two newly formed DNA helixes to uncoil from each
other were it not for some special mechanism. This
uncoiling is achieved by DNA helicase enzymes that
break the hydrogen bonding between the base pairs
of the DNA, permitting the two strands to separate
into a Y shape known as the replication fork, the
area that will be the template for replication to be-
gin.
DNA is directional in both strands, signified by a 5′
and 3′ end (see Figure 3-15). Replication progresses
only in the 5′ to 3′ direction. At the replication fork
one strand, the leading strand, is oriented in the 3′
to 5′ direction, toward the replication fork, while the
lagging strand is oriented 5′ to 3′, away from the rep-
lication fork. Because of their different orientations,
the two strands are replicated differently.
5. Primer binding. Once the DNA strands have been
separated, a short piece of RNA called an RNA
primer binds to the 3′ end of the leading strand.
Primers are generated by the enzyme DNA primase.
42
DNA
polymerase
Leading strand
5’
3’
Okazaki DNA ligase
fragment
5’
3’
DNA
polymerase Lagging strand
Primers always bind as the starting point for DNA
replication.
6. Elongation. DNA polymerases are responsible for
creating the new strand by a process called elon-
gation. Because replication proceeds in the 5′ to 3′
direction on the leading strand, the newly formed
strand is continuous. The lagging strand begins
replication by binding with multiple primers that
are only several bases apart. DNA polymerase then
adds pieces of DNA, called Okazaki fragments, to
the strand between primers. This process of repli-
cation is discontinuous because the newly created
Okazaki fragments are not yet connected. An en-
zyme, DNA ligase, joins the Okazaki fragments to
form a single unified strand.
7. Termination. After the continuous and discontinu-
ous strands are both formed, the enzyme exonu-
clease removes the RNA primers from the original
strands, and the primers are replaced with appro-
priate bases. Another exonuclease “proofreads” the
newly formed DNA, checking and clipping off any
mismatched or unpaired residues.
Another enzyme, topoisomerase, can transiently break
the phosphodiester bond in the backbone of the DNA
strand to prevent the DNA in front of the replication fork
from being overwound. This reaction is reversible, and the
phosphodiester bond reforms as the topoisomerase leaves.
Once completed, the parent strand and its comple-
mentary DNA strand coils into the double helix shape.
The process of replication therefore produces two DNA
molecules, each with one strand from the parent DNA
and one new strand. For this reason, DNA replication is
often described as semiconservative; half of the chain is
part of the original DNA molecule and half is brand new.
DNA Repair, DNA “Proofreading,” and “Mutation.”
During the hour or so between DNA replication and
Another random document with
no related content on Scribd:
thickened triradiate rod of specialised cuticle (Fig. 62); these fins,
however, do not run far down the body. As a rule the cuticle is quite
smooth, but it may be ringed, as in Filaria laticaudata and in F.
denticulata; and the rings may bear backwardly-projecting teeth.

The skin of Nematodes consists of three layers—(i.) the above-

mentioned cuticle, which is presumably secreted by (ii.) the sub-
cuticle or epidermis which underlies it; the latter surrounds in its turn
(iii.) the muscular layer.

The nature of the sub-cuticle is one of the debateable points in the

morphology of the Nematoda. No cell outlines have been detected in
it, although nuclei are scattered through it; it is in fact a syncytium, or
protoplasmic mass in which cell limits cannot be distinguished. Many
of the cells forming it have broken down into fibrils, and these form a
close meshwork, which is occasionally specialised, as, for instance,
round the nerve-cords. Along the median dorsal and ventral lines,
and along the lateral lines, this tissue is heaped up in such a way as
to divide the enclosed muscle-cells into four quadrants. These
thickenings surround dorsally and ventrally a specialised nerve-cord,
and laterally the excretory canals.

According to Jammes[155] this lack of differentiation in the sub-

cuticular layer is caused by the early appearance of the cuticle,
which he thinks is necessitated, at any rate in many of the parasitic
forms, by the action which the digestive juices of the host would
have on the otherwise unprotected body-wall.
 Fig. 62.—A transverse section through the body of Ascaris transfuga
Rud., in the region of the oesophagus: a, the muscular
oesophagus with its triradiate lumen; b, the cuticle; c, the sub-
cuticle; d, the muscular layer; e, the lateral nerves running in the
lateral line; f, the excretory canal; g, the dorsal, and h, the ventral
nerve; i, the triradiate rod in the fin.

The nervous system, according to the same writer, is of the same

nature as this sub-cuticular tissue, only it is more differentiated, or
perhaps we should say it has retained more of the primitive cellular
character of the embryonic tissue. The fibres of the sub-cuticular
tissue are closely connected with the fibrils which compose the
spongioplasm (Fig. 64, d) of the muscles,[156] and form also the
sheaths of the various nerves; in fact the passage of these fibrils into
the nerves is so gradual that it is impossible to make any separation
between them.

The Nervous System.—The central organ of the nervous system is

the circumoesophageal ring which surrounds the pharynx, close to
the anterior end of the body, in A. megalocephala 1½ to 2 mm.
behind the mouth.[157] Ganglion cells are found in the ring, but they
are not numerous, and are chiefly aggregated round the points of
origin of the nerves.

Six short nerves, three on each side of the median line, run forward
from the ring, a pair of these ending in each of the three papillae
which surround the mouth.

Behind, the nerve-ring gives off six main nerve trunks, of which the
dorsal and ventral nerves are usually the largest. These run in the
median dorsal and ventral thickenings of the sub-cuticular tissue,
and are connected one with another by numerous fine lateral
branches running through the sub-cuticle.
 Fig. 63.—Diagram of the nervous system at the two ends of the body in
Ascaris megalocephala Cloq., ♂ . (After Hesse.) a,
Circumoesophageal nerve-ring; b, opening of excretory ducts; c,
dorsal nerve; d, dorso-lateral nerve; e, ventro-lateral nerve
becoming the bursal nerve posteriorly; f, the ventral nerve; g,
cloacal opening; h, sub-cuticular nerves running from c to f; k,
spicules.

The lateral nerves, which consist of two or four bundles, one or two
lying dorsal and one or two ventral to each excretory canal, have a
double origin. The dorsal branches arise directly from the nerve-ring,
and at their point of origin there is a considerable accumulation of
ganglion cells, from which two commissures on each side run into
the ventral nerve (Fig. 63, f). The ventral branches arise from the
ventral nerve-cord immediately in front of the excretory pore. At the
posterior end the lateral nerves pass into the two branches into
which the ventral nerve divides. Just before the point where the
ventral nerve splits it swells out into an anal ganglion situated just in
front of the anus. In the male[158] this anal ganglion gives off two
lateral nerves which pass round the cloaca and form a ring, and in
this sex the ventro-lateral nerve, which is much strengthened by
fibres from the ventral nerve, and has received, owing to the
mistaken impression that it was a special nervus recurrens, the
name of the "bursal nerve," gives off numerous branches to the
sense papillae which are found in this region of the body and on the
tail. The arrangement of these parts is shown in Fig. 63.

Sense organs are but poorly developed in the Nematoda, as is usual

in animals which are, as a rule, either parasitic or live underground.
Eyes, consisting of masses of dark pigment with or without a lens,
occur in the neighbourhood of the circumoesophageal nerve-ring in
some free-living forms. Leuckart described as possible auditory
organs certain giant-cells lying near the orifice of the excretory ducts.
Later research has shown these cells to have some phagocytic
action on the contents of the body-cavity. The chief sense organs are
the papillae, of which in A. megalocephala there are two kinds, the
lip papillae being distinguished from the genital papillae by the fact
that the nerve supplying them ends in a fine point and pierces the
cuticle in the former case, whilst in the latter it swells out into an
"end-organ," which is always covered by a layer of cuticle, though
sometimes by a very thin one.

Muscular System.—The muscular system is one of the most

characteristic features of the Nematoda, both as regards the
histology of the muscle-cells and the way in which the cells are
arranged.

Each muscle-cell is of considerable size, and is of the shape of a

somewhat flattened spindle produced into a process near the middle.
Each end of the spindle cell is said to be continuous with the fibrils of
the sub-cuticular layer.[159] The muscle-cell consists of two portions,
a contractile part which lies next the sub-cuticle, and which usually,
to some extent, wraps round the second or medullary half. The latter
consists of a fibrillar spongioplasm, in the meshes of which lies a
clear structureless hyaloplasm. The nucleus always lies in the
medullary half.

The contractile portion consists of a number of columns, very

regularly arranged in two rows and close together, but allowing
sufficient space between adjacent columns for fibrils of the
spongioplasm to penetrate; and these become continuous with the
fibrils of the sub-cuticle, which is thus intimately connected with both
nervous and muscular systems.

The medullary portion of the cell varies greatly in size; it may stretch
far into the body-cavity, which may be thereby almost occluded, or it
may be flattened out, leaving a large space around the alimentary
canal. At one point, usually about its middle, it is produced into a
process, which bends inwards towards the dorsal or ventral nerve-
cord, and by means of this process the muscle receives its nerve
supply.

In most Nematodes there are numerous muscle-cells to be seen in

any transverse section, forming a layer within the sub-cuticle, and
broken up into four quadrants (Fig. 62) by the projection of the
dorsal, ventral, and lateral thickenings of the sub-cuticular tissue. In
some genera, however, such as Oxyuris, Strongylus, Pelodera,
Leptodera, etc., there are but eight muscle-cells in a row, two in each
quadrant. Such genera are classed together by Schneider,[160] and
termed Meromyarii (vide p. 137).

Fig. 64.—A, transverse section through the centre of a muscle-cell; B,

the same through a nerve fibre showing the sub-cuticular fibres
running into the sheath. (After Rohde.) a, Cuticle; b, sub-cuticular
fibres continuous with d; c, contractile columns; d, network of
spongioplasm; e, nucleus.

In addition to the characteristic muscles of the body-wall there are

others, such as those which move the spicules in the male, which
cross the body-cavity obliquely near the anus, and such as sphincter
muscles near the latter orifice, which have not the characteristic
arrangement of contractile and medullary parts described above.
The Body-Cavity.—The skin of a Nematode, as described above,
contains most of the important organs of the body within its
thickness. The chief muscular system, the nervous system with its
sense organs, and the excretory organs are all embedded in or form
part of the skin, which in its turn encloses a cavity—the body-cavity
—in which the other two systems of organs which are found in
Nematodes lie. These are the digestive system and the reproductive
system.

The body-cavity is continuous from one end of the animal to the

other, and is in no case divided up into compartments by the
presence of septa or mesenteries. It contains a coagulable fluid with
numerous corpuscles; this is, as a rule, colourless, but in Syngamus
trachealis Sieb. (Fig. 70), which lives on blood, the haemoglobin of
its host tinges it red, though the colour is said to disappear if the
parasite be isolated and starved.

The morphological nature of this body-cavity affords an interesting

problem. It is not a true coelom, such as exists in the earthworm,
since it is not surrounded by mesoderm, nor do the excretory organs,
with the possible exception of one or two genera, open into it, nor do
the generative cells arise from its walls. Essentially it is a space
between the mesodermic muscle-cells which line the skin and the
endodermic cells of the alimentary canal, and although in many of its
functions it resembles the coelom of other animals, its morphological
character is quite different.

There are no respiratory or circulatory organs in the Nematoda;

possibly the fluid in the body-cavity acts, to some extent, as a carrier
of oxygen, but from the inert and almost vegetative life of these
animals it seems probable that their respiratory processes are slow,
and in fact Bunge[161] has shown that Ascaris mystax, found in the
intestine of the cat, will live for four or five days in media quite free
from oxygen, and that A. acus from the pike will live and exhibit
movements in the same media for from four to six days.
The Digestive System.—The mouth of the Nematoda is usually
anterior and terminal, and is surrounded by from two to six projecting
lips, the most common number being three. These lips are well
provided with sense papillae. The mouth leads into an alimentary
canal, which with hardly an exception runs straight through the body
to the anus without twists or loops. The anus is usually placed
ventrally and is not terminal, but in Trichina and Trichocephalus it is
at the end of the body, and in Mermis, where the several parts of the
alimentary canal are said not to communicate, it is absent altogether.
Ichthyonema, Dracunculus, Allantonema, Atractonema, and other
Filariae are also aproctous.

The alimentary canal is divisible into three parts—(i.) the

oesophagus, (ii.) the intestine, and (iii.) the rectum. The suctorial
oesophagus is a very muscular, thick-walled tube, lined with cuticle
continuous with that which covers the body, and like it cast from time
to time. Its lumen is usually much reduced, and is almost invariably
triangular or triradiate in section (Fig. 62). In many genera the hinder
end of the oesophagus is swollen into a muscular bulb, which is
armed with teeth in Heterakis, Oxyuris, Pelodera, Leptodera, etc.
Other species, such as Tylenchus, Aphelenchus, Dorylaimus, are
armed with a spear, which in Onyx,[162] a genus recently described
and allied to the last named, is borne on a special bulb. The use of
the spear is to pierce the tissue upon the juices of which the animal
lives. A gland lies embedded in the thick walls of the oesophagus,
and opens into its lumen by a fine tube. This was first described by
Schneider[163] in A. megalocephala, and more recently it has been
found by Hamann[164] in a number of Ascaridae and Strongylidae
from the Adriatic, and also in Lecanocephalus.

With a few exceptions, such as Mermis, where it is blind, the

oesophagus opens posteriorly into the intestine. This is a somewhat
flattened tube, whose shape and position are often altered by the
development of the generative organs. Its wall consists of a single
layer of columnar cells, with large nuclei coated internally and
externally by a layer of cuticle. The inner layer of cuticle is usually
perforated by very numerous minute pores. In some species the
intestine is degenerate, in Mermis it is a closed tube opening neither
into the oesophagus nor into the rectum; in Trichina spiralis and in
the larva of Tylenchus tritici it consists of a single row of cells
perforated by a duct, but in the adult of the last named there are
many cells in a transverse section.

Fig. 65.—A longitudinal section through the body of Strongylus filaria

Rud. (From O. Augstein.[165]) A portion of the body, on each side
of the excretory pore, is seen in optical section. a, Mouth; b,
oesophagus; c, intestine; d, excretory canal; e, excretory pore,
and the opening of the poison glands, i; f, circumoesophageal
nerve-ring; g, ventral nerve; h, dorsal nerve; i, unicellular poison
glands; k, ovary, with the ova separate; l, oviduct; m, uterus, the
first egg in the uterus is surrounded by spermatozoa; n, opening
of uterus; o, inner end of ovary with the ova undifferentiated.

In some genera, Leptodera and Pelodera, the lumen of the intestine

at any one level is bounded by two horseshoe-shaped cells, but by
far the commonest arrangement is a tube formed of fairly numerous
columnar cells crowded with granules and with large nuclei.

The rectum is usually short; its cuticular lining, like that of the
oesophagus, is cast at intervals. At its anterior end there is usually a
sphincter muscle, and its walls are divaricated by muscular strands
which run from it to the body-wall. The anus is a transverse slit,
which in the male Strongylidae is surrounded by a funnel-shaped
membrane.

The food of Nematodes seems to be almost entirely fluid, and

consists, at any rate in the parasitic forms, of the elaborated juices of
their hosts. Little is known about the nutriment of the free-living
forms.

The Excretory System.—The excretory organs are peculiar, and,

like many other Nematode structures, do not fall readily into line with
what is known of similar organs in other animals. They consist of two
canals embedded in the lateral thickenings of the sub-cuticular
tissue. The canals end blindly behind, but near the anterior end of
the body they bend inwards, and after uniting, open by a common
pore situated in the middle ventral line, a little way behind the mouth.
The lateral canals are in some cases continued in front of the
transverse branch, and they then end blindly in the head. The walls
of these canals consist of an internal, structureless, refractive layer
surrounded by a granular layer with nuclei. They contain a fluid, but
nothing is known of its composition.

An interesting divergence from the usual form of excretory organ has

been described by Hamann[166] in the genus Lecanocephalus. Here
there is only one canal, the right; anteriorly this bends towards the
ventral surface and opens by a small median pore close behind the
nerve-ring. Posteriorly the canal does not extend much beyond the
middle of the body, where it forms a coiled mass, and diminishing in
size, opens into the body-cavity. The same author also states that
both canals in Dochmius have a similar internal opening; these
observations, if confirmed,[167] show a conformity to the ordinary
structure of excretory organs which was not supposed to exist in the
lateral canals of the Nematoda.

The Reproductive Organs.—With the exception of the genera

Angiostomum, Pelodytes, and of Rhabdonema nigrovenosum, which
are physiologically hermaphrodite and self-impregnating, the
Nematodes have separate sexes. The males are, as a rule, smaller
than the females, and may usually be distinguished by the posterior
end of the body being curved towards the ventral surface; a genital
bursa, and one or more spicules are often found in this sex. Further,
the position of the genital opening differs; in the male the vas
deferens opens on the ventral surface of the rectum close to the
anus, but the oviduct in the female opens in the ventral middle line,
usually near the middle of the body, but sometimes close behind the
excretory pore, or in some Strongylidae just in front of the anus. The
tail of the male bears very numerous papillae, which are of
considerable systematic importance.

Fig. 66.—Ascaris lumbricoides Cloq. ♂, natural size, cut open along the
dorsal middle line. a, Oesophagus; b, intestine; c, testis; d, vas
deferens; h, lateral excretory canals.

With rare exceptions, e.g. Filaria attenuata, where it is double, the

male reproductive organ consists of a single tube divisible into a
testis proper, a vas deferens, a vesicula seminalis, where the
spermatozoa are stored up, and a ductus ejaculatorius. The tube
stretches through the body in a straight line in the small free-living
forms, but is thrown into loops and coils in the larger parasitic
Nematodes. Within the testis the mother-cells of the spermatozoa
are attached to a rhachis or axial cord; the mother-cells divide, and
their products ultimately form spermatozoa. The latter have a very
peculiar shape; in accordance with the universal absence of cilia in
the Nematoda the spermatozoon has no flagellum, and at first
consists of a spherical nucleated cell, on one side of which a cap or
covering of some refractive substance appears. The cap elongates
and becomes conical, whilst the protoplasmic portion of the
spermatozoon throws out pseudopodia and becomes amoeboid, but
ultimately rounds itself off again. The spermatozoa do not attain
maturity until they reach the uterus of the female.

The internal female reproductive organs are, with few exceptions

(Trichina, etc.), double, but the vagina, which is lined with cuticle
continuous with that covering the body, is always single. They are
usually much coiled, and may be divided into ovary, oviduct, and
uterus. The ova arise from a polynucleated mass of protoplasm or
syncytium (Fig. 65, o) at the upper end, and acquire distinctness as
they approach the oviduct. Fertilisation takes place in the uterus, but
the segmentation may not begin until some time after the eggs are
laid; in Dochmius, however, it is well advanced at this period, and in
many genera, e.g. Pseudalius, Trichina, Dracunculus, etc., the whole
development of the larva takes place in the body of the mother.
 Fig. 67.—Ascaris lumbricoides Cloq. ♀, natural size, cut open along the
median dorsal line to show the internal organs. a, The muscular
oesophagus; b, the intestine; c, the ovary; d, the uterus; e, the
vagina; f, the external opening; h, the excretory canals; i, their
opening.

Embryology.—The eggs of many of the parasitic forms require a

considerable degree of warmth to develop. Those of Ascaris
lumbricoides require a temperature of 20° C., those of
Trichocephalus 22.5° C., and those of Oxyuris vermicularis, 40° C.
The latter develop in a few hours, the eggs of Dochmius in a few
days, whilst those of A. lumbricoides take weeks or even months,
and the young of Trichocephalus seldom develop within a year.[168]
The ova only develop in a damp atmosphere, and they can be
arrested at almost any stage, and for considerable periods, by
desiccation.

Our knowledge of the processes by which the fertilised egg-cell

develops into the larva is very imperfect. As a rule the segmentation
is complete and equal; it results in the formation of a blastula, which
may take the form of a hollow sphere of cells—A. megalocephala—
or the cavity may be reduced, and the blastula may consist of a
double-layered plate, as in Cucullanus.[169] The distinction into cells
which will form the three embryonic layers, the ectoderm, mesoderm,
and endoderm, is very early evident,—in the eight-cell stage. By the
growth of one side of the blastula and the tucking in of the other the
blastula becomes converted into a gastrula, which is a two-layered
stage with a cavity opening to the exterior by a pore termed the
blastopore. In Nematodes the blastopore is elongated and slit-like; it
either forms the mouth (Cucullanus) or closes from behind forwards,
the mouth ultimately arising at the point where the blastopore finally
closed (Rhabdonema nigrovenosum). The mesodermal cells lie
between the ectoderm and the endoderm; they ultimately develop
into the muscles of the body-wall, the lateral excretory canals, and
the reproductive organs; the last-named two systems arise each[170]
from a single cell. The nervous system arises from the ectoderm,
which also forms the sub-cuticle, and is turned in slightly at the
mouth and anus; the remainder of the alimentary canal develops
from the endoderm.

The post-embryonic development, which is very variable, and in

many cases very extraordinary, will be dealt with under the several
families.

Classification.—The classification of the Nematodes is a matter of

very considerable difficulty; their structure is unusually monotonous,
and, owing perhaps to their largely parasitic mode of life, they show
practically none of those external features which are so useful to the
systematist in other groups. Schneider in his Monograph divides the
group into three subdivisions—(i.) the Polymyarii, in which
numerous muscle cells are seen in a transverse section; (ii.) the
Meromyarii, in which only eight are seen, two in each quadrant; and
(iii.) the Holomyarii, in which the muscles are either not divided, or
only divided by longitudinal lines. This grouping has, however, to
some extent broken down, since Bütschli[171] and others have
shown that the third subdivision is founded on insufficient
observation, whilst the first two include, in different subdivisions,
Nematodes which are closely allied in all respects except as regards
their muscle cells.

The details of the life-history have been used by other writers as a

basis of classification. Linstow[172] enumerates fourteen distinct
modifications of the post-embryonic development (vide p. 159), and
Örley[173] has grouped these under three headings. The animals
which fall under each group to some extent resemble one another in
structure. Örley's groups are:—

(i.) Nematozoa.—Thread-worms with free larval life, the mature

forms being parasitic in animals. Enormous numbers of eggs are
produced, and the development is indirect. The genital organs are
complicated by many convolutions.

(ii.) Rhabditiformae.—Small, as a rule microscopic, thread-worms,

usually living free, but rarely parasitic. They become sexually mature
only in decomposing organic substances, or in earth saturated with
such substances. They live gregariously and do not produce
immense numbers of ova. The metamorphosis is slight, or is
complicated by sexual metamorphosis. The oesophagus has two
dilatations. The genital tubes are simple and not coiled.

(iii.) Anguillulidae.—Small microscopic thread-worms, with a free

existence in mould or water, throughout all stages. They produce
large eggs. They are provided with a caudal sucker and bristles,
sometimes with eyes and other structures characteristic of a free life.
Genital tube simple and not coiled.

The disadvantage of such a system is, that to accurately place a

specimen in its proper class we must be acquainted with its life-
history, and this is known in but few cases.

The determination of the species to which a Nematode belongs is a

matter of considerable difficulty. Amongst the more important
features for purposes of classification are the arrangement of the
muscles, the character of the tail in the male, especially when
papillae are present, the number and the size of the spicules, and
the arrangement of the lips and mouth-parts generally.

Cobb[174] has recently devised an ingenious formula in which

measurements of different parts of the body appear as percentages
of the whole length of the body. The nature of this will be understood
by reference to Fig. 68. Such a formula should, however, be used
with caution, since it rests on the assumption that the proportions of
the various parts of the body are constant in different individuals, and
it is by no means certain that this is the case.

Fig. 68.—Diagram to explain the descriptive formula used for

Nematodes. (From Cobb.) 6, 7, 8, 10, 6 are the transverse
measurements, while 7, 14, 28, 50, 88 are the corresponding
longitudinal measurements. The formula in this case is
7 14 28 50 88
6 7 8 10 6

The unit of measurement is the one-hundredth part of the length of the

worm. The measurements are therefore percentages of the
length.
The measurements are taken with the animal viewed in profile; the first
is taken at the base of the oesophagus, the second at the nerve-
ring, the third at the cardiac constriction, the fourth at the vulva in
females and at the middle in males, the fifth at the anus.

Taking everything into consideration, it has seemed advisable in the

following systematic account of the Nematoda to abandon the larger
groups, and to deal directly with the families. Claus distinguishes
seven of these, and the diagnoses given at the head of each are
mainly taken from his Grundzüge der Zoologie.[175]
 I. Family Ascaridae.

Body rather stout. A dorsal and two ventro-lateral lips, bearing

papillae. Buccal cavity distinct, seldom provided with chitinous
armature. The oesophagus often has two dilatations. The tail of the
male is ventrally curved, and usually there are two horny spicules.
The Ascaridae are found in the intestines of their respective hosts.

Genera: Ascaris, Heterakis, Oxyuris, Nematoxys, Oxysoma, and

many others.

Von Linstow[176] enumerates over 250 species of Ascaris, of which it

will only be possible to mention here one or two. They are all
parasitic in Vertebrata.

A. lumbricoides Linn. is one of the largest known Nematodes ♂ = 4-6

in., ♀ = 10-14 in.; Figs. 66 and 67). It is a common parasite in man,
and has been found in the ox. It is now generally recognised as the
same parasite which inhabits the pig, and which Dujardin regarded
as specifically distinct, and named A. suillae. In the latter host,
however, it never attains the dimensions it does in man. It inhabits
the upper and middle parts of the small intestine, and has been
known to escape into the body-cavity and set up abscesses there, or
to make its way into the stomach, and to be voided through the
mouth. It is practically cosmopolitan in distribution, and is very
common in Japan—Baely found it in twenty-one out of twenty-three
post-mortems—and in Tonquin and tropical Africa. Heller[177] states
that no one is free from these worms in Finland, and they are
common wherever there is a plentiful water supply, as in the marshy
districts of Holland and Sweden. In Iceland alone they seem absent.
When examined alive they give off an irritating vapour which
seriously affects some observers, causing catarrhal symptoms,
which in Bastian's case lasted six weeks. The usual number found in
one host is small, one to six or eight, but cases are on record where
many hundreds occurred in one person.
The details of the life-history of this form are not yet completely
worked out. The eggs leave the body of the host with the excreta,
and formerly it was thought they re-entered the alimentary canal in
drinking-water, etc., and there developed into the adult without
change of host. This view has been combated by Leuckart, who
failed to rear the Nematodes by direct feeding, and it has been
noticed that the youngest parasites found in the intestine are already
2 to 3 mm. long. Von Linstow has recently suggested that the larval
stages may be hatched out in the body of the millipede Julus
guttulatus, whose habits might easily lead it to eat the eggs of the
parasite in manured gardens, etc., and which is itself sometimes
unconsciously eaten when hidden in fruit or vegetables. This would
account for the frequent presence of the parasite in pigs, and also for
the fact that in man it is commonest in children who are apt to eat
windfalls, and in maniacs and people with perverted tastes.

A. megalocephala, which is found in the horse, ass, zebra, ox, etc.,

attains even greater dimensions than the foregoing. The male rarely
exceeds 7 inches in length, but the female sometimes reaches 17
inches. They are found in the small intestine of their hosts.
Cobbold[178] succeeded in rearing larvae which attained a high
degree of organisation when the eggs were placed amongst moist
horse-dung, and it seems probable that the larvae pass into the body
of their hosts in drinking water; at any rate no intermediate host has
yet been found, and Davaine, who fed cows, and Leuckart, who fed
horses with the unhatched eggs, both failed to infect the animals
they experimented on. A. mystax, which lives in cats, dogs, and
other Carnivora, has also been found in man. It is provided with fin-
like extensions on the side of its head (cf. Fig. 62), and varies much
in size in different hosts. When first found in man it received the
name of A. alata. It becomes sexually mature in about three weeks.

One of the most remarkable cycles of development amongst the

many curious life-histories met with amongst Nematodes, is that
presented by Rhabdonema (Ascaris) nigrovenosum. The free form of
this, formerly known as a distinct species, Rhabditis nigrovenosa,
lives in the excrement of frogs, and attains sexual maturity in a very
short time. The sexes pair, and the fertilised ova give rise to embryos
which hatch out within the body of the mother, and then begin to
devour her internal organs. After the destruction of the mother, the
embryos escape and live in water or slime, and sometimes burrow
into water snails, but they undergo no change until swallowed by a
frog. Then they make their way into its lungs and grow enormously,
attaining a length of almost an inch. This form, parasitic in the frog, is
a protandrous hermaphrodite, which first produces spermatozoa and
afterwards ova; the latter are fertilised by the spermatozoa, and give
rise to rhabditiform embryos, which escape by the alimentary canal
and form the free-living sexual stage mentioned above. Thus in the
life-history of this form we find an alternation of generation, a sexual
free-living form alternating with a hermaphrodite parasitic form.

Of the enormous number of other species of the genus, only a very

few can be mentioned. A. transfuga Rud. inhabits bears; A.
leptoptera Rud., lions; A. ferox H. and Ehrbg., Hyracoidea; A.
depressa Rud., vultures; A. rubicunda Schn., pythons; A. sulcata
Rud., turtles; A. mucronata Schn., the cod and pike; A. incurva Rud.,
the sword-fish.
 Fig. 69.—A male and female Oxyuris diesingi Ham. in copula, × 60. a,
Anus; b, oesophagus; c, bulb; d, testis; e, intestine; f, ovary. (From
Galeb.[179])

Oxyuris is Meromyarian (see p. 137), and is characterised by the

long capillary tail of the female. It includes another human parasite,
O. vermicularis, and it is one which it is difficult to get rid of. The
female has the characteristic tail and is about 10 mm. long. The male
is smaller. They are found in the caecum and rectum of man, and
cause great irritation and sometimes serious functional disturbance.
The eggs are laid in immense numbers but perish in water. If whilst
still in the egg-shell the larvae are swallowed on fruit or raw
vegetables, etc., they are set free in the stomach and small intestine
by the action of the digestive secretions. The distribution of this
parasite is universal. Besides numerous species that inhabit the
alimentary canal of Vertebrates, such as O. ambigua Rud., found in
hares and rabbits; O. curvula Rud., in the caecum of horses; O.
megatyphlon Rud., in iguanas; several species inhabit the rectum of
insects, such as O. blattae, O. diesingi, O. blatticola, found in the
cockroach; O. spirotheca, and O. hydrophili in the water beetle
Hydrophilus.[180]

The genus Nematoxys has the most complex arrangement of

muscles of any Meromyarian, and forms a transition to the
Polymyarian type. The whole body of both sexes is covered with
numerous irregularly scattered papillae. The members of this genus
have hitherto been found in snakes, Amphibia, and eels; there are
but few species.

Oxysoma is another small genus with but three species, found in the
intestines of opossums, frogs, and turtles respectively.

II. Family Strongylidae.

Mouth surrounded by papillae; an armature of teeth or spines often
present. The chitinous lining of the intestine projects into the interior
as ridges. No oesophageal bulb. The male orifice at the posterior
end of the body is surrounded by a bell-shaped bursa.

Genera: Eustrongylus, Strongylus, Dochmius, Sclerostomum,

Cucullanus, Syngamus, Pseudalius, Ollulanus, and others.

The genus Eustrongylus includes two species, E. gigas Rud. and E.

tubifex Nitsch. The former attains in the female the gigantic length of
860 mm., with a breadth of 7 mm. and a weight of over 40 grs.[181]
The male is a quarter to a third as long as the female. This parasite
inhabits the kidney capsules of carnivorous animals, especially of
those that eat fish, such as dogs, seals, etc., and has occasionally
been found in man, the horse, and the deer. It frequently destroys
the substance of the kidney. The worms are red in colour. The eggs
die when exposed to desiccation for a few days, but have been kept
alive for fifteen months in water; it is believed by Schneider and
Leuckart that they are eaten by fish, and that the larvae form the
Filaria cystica found in the peritoneal membrane of the fishes
Galaxias scriba and Symbranchus laticaudatus, and that they pass
into their final host, where they become sexually mature, by the latter
eating raw fish. E. tubifex is found in aquatic birds, e.g. ducks,
grebes, and divers, etc.

The genus Strongylus is easily recognised by its conspicuous genital

bursa, strengthened by variously arranged ridges which are of
specific value. There are numerous species, found in man and many
other mammals, and also in birds and reptiles. Some species inhabit
the intestine, others form aneurisms in the large blood-vessels, and
cause considerable mortality amongst horses; others live in the
tracheae and lungs of cattle and sheep, their presence often causing
great loss to the farmer. No intermediate host has been satisfactorily
demonstrated; the larvae live in damp earth, and it seems almost
certain that they pass directly into their host with its food.